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Archive for the ‘Proteomics’ Category

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

Curators: Dr. Stephen J. Williams and Aviva Lev-Ari, PhD, RN

DeepMind creates ‘transformative’ map of human proteins drawn by artificial intelligence

DeepMind plans to release hundreds of millions of protein structures for free

James Vincent July 22, 2021 11:00 am

AI research lab DeepMind has created the most comprehensive map of human proteins to date using artificial intelligence. The company, a subsidiary of Google-parent Alphabet, is releasing the data for free, with some scientists comparing the potential impact of the work to that of the Human Genome Project, an international effort to map every human gene.

Proteins are long, complex molecules that perform numerous tasks in the body, from building tissue to fighting disease. Their purpose is dictated by their structure, which folds like origami into complex and irregular shapes. Understanding how a protein folds helps explain its function, which in turn helps scientists with a range of tasks — from pursuing fundamental research on how the body works, to designing new medicines and treatments.
 “the culmination of the entire 10-year-plus lifetime of DeepMind” 
Previously, determining the structure of a protein relied on expensive and time-consuming experiments. But last year DeepMind showed it can produce accurate predictions of a protein’s structure using AI software called AlphaFold. Now, the company is releasing hundreds of thousands of predictions made by the program to the public.
“I see this as the culmination of the entire 10-year-plus lifetime of DeepMind,” company CEO and co-founder Demis Hassabis told The Verge. “From the beginning, this is what we set out to do: to make breakthroughs in AI, test that on games like Go and Atari, [and] apply that to real-world problems, to see if we can accelerate scientific breakthroughs and use those to benefit humanity.”



Two examples of protein structures predicted by AlphaFold (in blue) compared with experimental results (in green). 
Image: DeepMind


There are currently around 180,000 protein structures available in the public domain, each produced by experimental methods and accessible through the Protein Data Bank. DeepMind is releasing predictions for the structure of some 350,000 proteins across 20 different organisms, including animals like mice and fruit flies, and bacteria like 
E. coli. (There is some overlap between DeepMind’s data and pre-existing protein structures, but exactly how much is difficult to quantify because of the nature of the models.) Most significantly, the release includes predictions for 98 percent of all human proteins, around 20,000 different structures, which are collectively known as the human proteome. It isn’t the first public dataset of human proteins, but it is the most comprehensive and accurate.

If they want, scientists can download the entire human proteome for themselves, says AlphaFold’s technical lead John Jumper. “There is a HumanProteome.zip effectively, I think it’s about 50 gigabytes in size,” Jumper tells The Verge. “You can put it on a flash drive if you want, though it wouldn’t do you much good without a computer for analysis!”
 “anyone can use it for anything” 
After launching this first tranche of data, DeepMind plans to keep adding to the store of proteins, which will be maintained by Europe’s flagship life sciences lab, the European Molecular Biology Laboratory (EMBL). By the end of the year, DeepMind hopes to release predictions for 100 million protein structures, a dataset that will be “transformative for our understanding of how life works,” according to Edith Heard, director general of the EMBL.
The data will be free in perpetuity for both scientific and commercial researchers, says Hassabis. “Anyone can use it for anything,” the DeepMind CEO noted at a press briefing. “They just need to credit the people involved in the citation.”

The benefits of protein folding


Understanding a protein’s structure is useful for scientists across a range of fields. The information can help design new medicines, synthesize novel enzymes that break down waste materials, and create crops that are resistant to viruses or extreme weather. Already, DeepMind’s protein predictions are being used for medical research, including studying the workings of SARS-CoV-2, the virus that causes COVID-19.
 “it will definitely have a huge impact for the scientific community” 
New data will speed these efforts, but scientists note it will still take a lot of time to turn this information into real-world results. “I don’t think it’s going to be something that changes the way patients are treated within the year, but it will definitely have a huge impact for the scientific community,” Marcelo C. Sousa, a professor at the University of Colorado’s biochemistry department, told The Verge.
Scientists will have to get used to having such information at their fingertips, says DeepMind senior research scientist Kathryn Tunyasuvunakool. “As a biologist, I can confirm we have no playbook for looking at even 20,000 structures, so this [amount of data] is hugely unexpected,” Tunyasuvunakool told The Verge. “To be analyzing hundreds of thousands of structures — it’s crazy.”

Notably, though, DeepMind’s software produces predictions of protein structures rather than experimentally determined models, which means that in some cases further work will be needed to verify the structure. DeepMind says it spent a lot of time building accuracy metrics into its AlphaFold software, which ranks how confident it is for each prediction.

Example protein structures predicted by AlphaFold.
Image: DeepMind
Predictions of protein structures are still hugely useful, though. Determining a protein’s structure through experimental methods is expensive, time-consuming, and relies on a lot of trial and error. That means even a low-confidence prediction can save scientists years of work by pointing them in the right direction for research.
Helen Walden, a professor of structural biology at the University of Glasgow, tells The Verge that DeepMind’s data will “significantly ease” research bottlenecks, but that “the laborious, resource-draining work of doing the biochemistry and biological evaluation of, for example, drug functions” will remain.
Sousa, who has previously used data from AlphaFold in his work, says for scientists the impact will be felt immediately. “In our collaboration we had with DeepMind, we had a dataset with a protein sample we’d had for 10 years, and we’d never got to the point of developing a model that fit,” he says. “DeepMind agreed to provide us with a structure, and they were able to solve the problem in 15 minutes after we’d been sitting on it for 10 years.”

Why protein folding is so difficult

Proteins are constructed from chains of amino acids, which come in 20 different varieties in the human body. As any individual protein can be comprised of hundreds of individual amino acids, each of which can fold and twist in different directions, it means a molecule’s final structure has an incredibly large number of possible configurations. One estimate is that the typical protein can be folded in 10^300 ways — that’s a 1 followed by 300 zeroes.

 Protein folding has been a “grand challenge” of biology for decades 

Because proteins are too small to examine with microscopes, scientists have had to indirectly determine their structure using expensive and complicated methods like nuclear magnetic resonance and X-ray crystallography. The idea of determining the structure of a protein simply by reading a list of its constituent amino acids has been long theorized but difficult to achieve, leading many to describe it as a “grand challenge” of biology.
In recent years, though, computational methods — particularly those using artificial intelligence — have suggested such analysis is possible. With these techniques, AI systems are trained on datasets of known protein structures and use this information to create their own predictions.

DeepMind’s AlphaFold software has significantly increased the accuracy of computational protein-folding, as shown by its performance in the CASP competition. 
Image: DeepMind
Many groups have been working on this problem for years, but DeepMind’s deep bench of AI talent and access to computing resources allowed it to accelerate progress dramatically. Last year, the company competed in an international protein-folding competition known as CASP and blew away the competition. Its results were so accurate that computational biologist John Moult, one of CASP’s co-founders, said that “in some sense the problem [of protein folding] is solved.”

DeepMind’s AlphaFold program has been upgraded since last year’s CASP competition and is now 16 times faster. “We can fold an average protein in a matter of minutes, most cases seconds,” says Hassabis. The company also released the underlying code for AlphaFold last week as open-source, allowing others to build on its work in the future.
Liam McGuffin, a professor at Reading University who developed some of the UK’s leading protein-folding software, praised the technical brilliance of AlphaFold, but also noted that the program’s success relied on decades of prior research and public data. “DeepMind has vast resources to keep this database up to date and they are better placed to do this than any single academic group,” McGuffin told The Verge. “I think academics would have got there in the end, but it would have been slower because we’re not as well resourced.”

Why does DeepMind care?

Many scientists The Verge spoke to noted the generosity of DeepMind in releasing this data for free. After all, the lab is owned by Google-parent Alphabet, which has been pouring huge amounts of resources into commercial healthcare projects. DeepMind itself loses a lot of money each year, and there have been numerous reports of tensions between the company and its parent firm over issues like research autonomy and commercial viability.

Hassabis, though, tells The Verge that the company always planned to make this information freely available, and that doing so is a fulfillment of DeepMind’s founding ethos. He stresses that DeepMind’s work is used in lots of places at Google — “almost anything you use, there’s some of our technology that’s part of that under the hood” — but that the company’s primary goal has always been fundamental research.
 “There’s many ways value can be attained.” 

“The agreement when we got acquired is that we are here primarily to advance the state of AGI and AI technologies and then use that to accelerate scientific breakthroughs,” says Hassabis. “[Alphabet] has plenty of divisions focused on making money,” he adds, noting that DeepMind’s focus on research “brings all sorts of benefits, in terms of prestige and goodwill for the scientific community. There’s many ways value can be attained.”
Hassabis predicts that AlphaFold is a sign of things to come — a project that shows the huge potential of artificial intelligence to handle messy problems like human biology.

“I think we’re at a really exciting moment,” he says. “In the next decade, we, and others in the AI field, are hoping to produce amazing breakthroughs that will genuinely accelerate solutions to the really big problems we have here on Earth.”


SOURCE

https://www.theverge.com/platform/amp/2021/7/22/22586578/deepmind-alphafold-ai-protein-folding-human-proteome-released-for-free?__twitter_impression=true

Potential Use of Protein Folding Predictions for Drug Discovery

PROTAC Technology: Opportunities and Challenges

  • Hongying Gao
  • Xiuyun Sun
  • Yu Rao*

Cite this: ACS Med. Chem. Lett. 2020, 11, 3, 237–240Publication Date:March 12, 2020https://doi.org/10.1021/acsmedchemlett.9b00597Copyright © 2020 American Chemical Society

Abstract

PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology companies. PROTACs opened a new chapter for novel drug development. However, any new technology will face many new problems and challenges. Perspectives on the potential opportunities and challenges of PROTACs will contribute to the research and development of new protein degradation drugs and degrader tools.

Although PROTAC technology has a bright future in drug development, it also has many challenges as follows:
(1)
Until now, there is only one example of PROTAC reported for an “undruggable” target; (18) more cases are needed to prove the advantages of PROTAC in “undruggable” targets in the future.
(2)
“Molecular glue”, existing in nature, represents the mechanism of stabilized protein–protein interactions through small molecule modulators of E3 ligases. For instance, auxin, the plant hormone, binds to the ligase SCF-TIR1 to drive recruitment of Aux/IAA proteins and subsequently triggers its degradation. In addition, some small molecules that induce targeted protein degradation through “molecular glue” mode of action have been reported. (21,22) Furthermore, it has been recently reported that some PROTACs may actually achieve target protein degradation via a mechanism that includes “molecular glue” or via “molecular glue” alone. (23) How to distinguish between these two mechanisms and how to combine them to work together is one of the challenges for future research.
(3)
Since PROTAC acts in a catalytic mode, traditional methods cannot accurately evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) properties of PROTACs. Thus, more studies are urgently needed to establish PK and PD evaluation systems for PROTACs.
(4)
How to quickly and effectively screen for target protein ligands that can be used in PROTACs, especially those targeting protein–protein interactions, is another challenge.
(5)
How to understand the degradation activity, selectivity, and possible off-target effects (based on different targets, different cell lines, and different animal models) and how to rationally design PROTACs etc. are still unclear.
(6)
The human genome encodes more than 600 E3 ubiquitin ligases. However, there are only very few E3 ligases (VHL, CRBN, cIAPs, and MDM2) used in the design of PROTACs. How to expand E3 ubiquitin ligase scope is another challenge faced in this area.

PROTAC technology is rapidly developing, and with the joint efforts of the vast number of scientists in both academia and industry, these problems shall be solved in the near future.

PROTACs have opened a new chapter for the development of new drugs and novel chemical knockdown tools and brought unprecedented opportunities to the industry and academia, which are mainly reflected in the following aspects:
(1)
Overcoming drug resistance of cancer. In addition to traditional chemotherapy, kinase inhibitors have been developing rapidly in the past 20 years. (12) Although kinase inhibitors are very effective in cancer therapy, patients often develop drug resistance and disease recurrence, consequently. PROTACs showed greater advantages in drug resistant cancers through degrading the whole target protein. For example, ARCC-4 targeting androgen receptor could overcome enzalutamide-resistant prostate cancer (13) and L18I targeting BTK could overcome C481S mutation. (14)
(2)
Eliminating both the enzymatic and nonenzymatic functions of kinase. Traditional small molecule inhibitors usually inhibit the enzymatic activity of the target, while PROTACs affect not only the enzymatic activity of the protein but also nonenzymatic activity by degrading the entire protein. For example, FAK possesses the kinase dependent enzymatic functions and kinase independent scaffold functions, but regulating the kinase activity does not successfully inhibit all FAK function. In 2018, a highly effective and selective FAK PROTAC reported by Craig M. Crews’ group showed a far superior activity to clinical candidate drug in cell migration and invasion. (15) Therefore, PROTAC can expand the druggable space of the existing targets and regulate proteins that are difficult to control by traditional small molecule inhibitors.
(3)
Degrade the “undruggable” protein target. At present, only 20–25% of the known protein targets (include kinases, G protein-coupled receptors (GPCRs), nuclear hormone receptors, and iron channels) can be targeted by using conventional drug discovery technologies. (16,17) The proteins that lack catalytic activity and/or have catalytic independent functions are still regarded as “undruggable” targets. The involvement of Signal Transducer and Activator of Transcription 3 (STAT3) in the multiple signaling pathway makes it an attractive therapeutic target; however, the lack of an obviously druggable site on the surface of STAT3 limited the development of STAT3 inhibitors. Thus, there are still no effective drugs directly targeting STAT3 approved by the Food and Drug Administration (FDA). In November 2019, Shaomeng Wang’s group first reported a potent PROTAC targeting STAT3 with potent biological activities in vitro and in vivo. (18) This successful case confirms the key potential of PROTAC technology, especially in the field of “undruggable” targets, such as K-Ras, a tricky tumor target activated by multiple mutations as G12A, G12C, G12D, G12S, G12 V, G13C, and G13D in the clinic. (19)
(4)
Fast and reversible chemical knockdown strategy in vivo. Traditional genetic protein knockout technologies, zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), or CRISPR-Cas9, usually have a long cycle, irreversible mode of action, and high cost, which brings a lot of inconvenience for research, especially in nonhuman primates. In addition, these genetic animal models sometimes produce phenotypic misunderstanding due to potential gene compensation or gene mutation. More importantly, the traditional genetic method cannot be used to study the function of embryonic-lethal genes in vivo. Unlike DNA-based protein knockout technology, PROTACs knock down target proteins directly, rather than acting at the genome level, and are suitable for the functional study of embryonic-lethal proteins in adult organisms. In addition, PROTACs provide exquisite temporal control, allowing the knockdown of a target protein at specific time points and enabling the recovery of the target protein after withdrawal of drug treatment. As a new, rapid and reversible chemical knockdown method, PROTAC can be used as an effective supplement to the existing genetic tools. (20)

SOURCE

PROTAC Technology: Opportunities and Challenges
  • Hongying Gao
  • Xiuyun Sun
  • Yu Rao*

Cite this: ACS Med. Chem. Lett. 2020, 11, 3, 237–240

Goal in Drug Design: Eliminating both the enzymatic and nonenzymatic functions of kinase.

Work-in-Progress

Induction and Inhibition of Protein in Galectins Drug Design

Work-in-Progress

Screening Proteins in DeepMind’s AlphaFold DataBase

Work-in-Progress

Other related research published in this Open Access Online Journal include the following:

Synthetic Biology in Drug Discovery

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression  for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

Read Full Post »

New avenues for research in membrane biology reveals the mobility of protein at work

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Membrane proteins (MPs) are proteins that exist in the plasma membrane and conduct a variety of biological functions such as ion transport, substrate transport, and signal transduction. MPs undergo function-related conformational changes on time intervals spanning from nanoseconds to seconds. Many MP structures have been solved thanks to recent developments in structural biology, particularly in single-particle cryo-Electron Microscopy (cryo-EM). Obtaining time-resolved dynamic information on MPs in their membrane surroundings, on the other hand, remains a significant difficulty.

OmpG (Open state) in a fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer. The protein is shown in light green cartoon. Lipids units are depicted in yellow, while their phosphate and choline groups are illustrated as orange and green van der Waals spheres, respectively. Potassium and chloride counterions are shown in green and purple, respectively. A continuous and semi-transparent cyan representation is used for water.
https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-021-24660-1/MediaObjects/41467_2021_24660_MOESM1_ESM.pdf

Weill Cornell Medicine (WCM) researchers have found that they can record high-speed protein movements while linking them to function. The accomplishment should allow scientists to examine proteins in more depth than ever before, and in theory, it should allow for the development of drugs that work better by hitting their protein targets much more effectively.

The researchers utilized High-Speed Atomic Force Microscopy (HS-AFM) to record the rapid motions of a channel protein and published in a report in Nature Communications on July 16. Such proteins generally create channel or tube-like structures in cell membranes, which open to allow molecules to flow under particular conditions. The researchers were able to record the channel protein’s rapid openings and closings with the same temporal resolution as single channel recordings, a typical technique for recording the intermittent passage of charged molecules through the channel.

Senior author Simon Scheuring, professor of physiology and biophysics in anesthesiology at WCM, said,

There has been a significant need for a tool like this that achieves such a high bandwidth that it can ‘see’ the structural variations of molecules as they work.

Researchers can now produce incredibly detailed photographs of molecules using techniques like X-ray crystallography and electron microscopy, showing their structures down to the atomic scale. The average or dominant structural positionings, or conformations, of the molecules, are depicted in these “images,” which are often calculated from thousands of individual photos. In that way, they’re similar to the long-exposure still photos from the dawn of photography.

Many molecules, on the other hand, are flexible and always-moving machinery rather than fixed structures. Scientists need to generate videos, not still photos, to reveal how such molecules move as they work, to see how their motion translates to function to catch their critical functional conformations, which may only exist for a brief moment. Current techniques for dynamic structural imaging, on the other hand, have several drawbacks, one of which being the requirement for fluorescent tags to be inserted on the molecules being photographed in many cases.

Scheuring and his lab were early adopters of the tag-free HS-AFM approach for studying molecular dynamics. The technology, which can photograph molecules in a liquid solution similar to a genuine cellular environment, employs an extremely sensitive probe, similar to a record player’s stylus, to feel its way over a molecule and therefore build up a picture of its structure. Standard HS-AFM isn’t quick enough to capture the high-speed dynamics of many proteins, but Scheuring and colleagues have developed a modified version, HS-AFM height spectroscopy (HS-AFM-HS), that works much faster by collecting dynamic changes in only one dimension: height.

The researchers used HS-AFM-HS to record the opening and closing of a relatively simple channel protein, OmpG, found in bacteria and widely studied as a model channel protein in the new study, led by the first author Raghavendar Reddy Sanganna Gari, a postdoctoral research associate in Scheuring’s laboratory. They were able to monitor OmpG gating at an effective rate of roughly 20,000 data points per second, seeing how it transitioned from open to closed states or vice versa as the acidity of the surrounding fluid varied.

More significantly, they were able to correlate structural dynamics with functional dynamics in a membrane protein of this size for the first time in a partnership with Crina Nimigean, professor of physiology and biophysics in anesthesiology, and her group at WCM.

The demonstration opens the door for a wider application of this method in basic biology and drug development.

Sanganna Gari stated,

We’re now in an exciting period of HS-AFM technology, for example using this technique to study how some drugs modulate the structural dynamics of the channel proteins they target.

Main Source

Technique reveals proteins moving as they work. By Jim Schnabel in Cornell Chronicle, August 16, 2021.

https://news.cornell.edu/stories/2021/08/technique-reveals-proteins-moving-they-work

Other Related Articles published in this Open Access Online Scientific Journal include the following:

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

https://pharmaceuticalintelligence.com/2021/04/10/cryo-em-disclosed-how-the-d614g-mutation-changes-sars-cov-2-spike-protein-structure/

Proteins, Imaging and Therapeutics

Larry H Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2015/10/01/proteins-imaging-and-therapeutics/

From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery

Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2021/07/19/from-high-throughput-assay-to-systems-biology-new-tools-for-drug-discovery/

Imaging break-through: Fusion of microscopy and mass spectrometry produces detailed map of protein distribution

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/03/18/imaging-break-through-fusion-of-microscopy-and-mass-spectrometry-produces-detailed-map-of-protein-distribution/

Advanced Microscopic Imaging

Larry H Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/02/07/advanced-microscopic-imaging/

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Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.

It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?

Scientists from the Harvard Medical School and the Boston Children’s Hospital help answer these urgent questions. The team reports its findings in the journal “Science a paper entitled Structural impact on SARS-CoV-2 spike protein by D614G substitution. The mutation rate of the SARS-CoV-2 virus has rapidly evolved over the past few months, especially at the Spike (S) protein region of the virus, where the maximum number of mutations have been observed by the virologists.

Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.


This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.

Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.

(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.

IMAGE SOURCE: Bing Chen, Ph.D., Boston Children’s Hospital, https://science.sciencemag.org/content/early/2021/03/16/science.abf2303

The work

The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.


Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.

IMAGE SOURCE:  Zhang J, et al., Science

Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection

Forthcoming directions by Bing Chen and Team

The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:

Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.

In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.

Main Source:

Abstract

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

https://science.sciencemag.org/content/early/2021/03/16/science.abf2303?rss=1

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Reporter : Irina Robu, PhD

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COVID-19 Sequel: Neurological Impact of Social isolation been linked to poorer physical and mental health

Reporter: Aviva Lev-Ari, PhD, RN

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Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

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COVID-19 T-cell immune response map, immunoSEQ T-MAP COVID for research of T-cell response to SARS-CoV-2 infection

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Tiny biologic drug to fight COVID-19 show promise in animal models

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Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/09/30/miniproteins-against-the-covid-19-spike-protein-may-be-therapeutic/

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First single-course ‘curative’ CRISPR Shot by Intellia rivals Alnylam, Ionis and Pfizer

Reporter: Aviva Lev-Ari, PhD, RN

 

Intellia to kick-start first single-course ‘curative’ CRISPR shot, as it hopes to beat rivals Alnylam, Ionis and Pfizer

It’s been a good year for Intellia: One of its founders, Jennifer Doudna, Ph.D., nabbed the Nobel Prize in Chemistry for her CRISPR research.

Now, the biotech she helped build is putting that to work, saying it now plans the world’s first clinical trial for a single-course therapy that “potentially halts and reverses” a condition known as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

This genetic disorder occurs when a person is born with a specific DNA mutation in the TTR gene, which causes the liver to produce a protein called transthyretin (TTR) in a misfolded form and build up in the body.

hATTR can manifest as polyneuropathy (hATTR-PN), which can lead to nerve damage, or cardiomyopathy (hATTR-CM), which involves heart muscle disease that can lead to heart failure.

This disorder has seen a lot of interest in recent years, with an RNAi approach from Alnylam seeing an approval for Onpattro a few years back, specifically for hATTR in adults with damage to peripheral nerves.

Ionis Pharmaceuticals and its rival RNAi drug Tegsedi also saw an approval in 2018 for a similar indication.

They both battle with Pfizer’s older med tafamidis, which has been approved in Europe for years in polyneuropathy, and the fight could spread to the U.S. soon.

The drug, now marketed as Vyndaqel and Vyndamax, snatched up an FDA nod last May to treat both hereditary and wild-type ATTR patients with a heart condition called cardiomyopathy.

While coming into an increasingly crowed R&D area, Intellia is looking for a next-gen approach, and has been given the go-ahead by regulators ion the U.K, to start a phase 1 this year.

The idea is for Intellia’s candidate NTLA-2001, which is also partnered with Regeneron, to go beyond its rivals and be the first curative treatment for ATTR.

By applying the company’s in vivo liver knockout technology, NTLA-2001 allows for the possibility of lifelong transthyretin (TTR) protein reduction after a single course of treatment. If this works, this could in essence cure patients of the their disease.

The 38-patient is set to start by year’s end.

“Starting our global NTLA-2001 Phase 1 trial for ATTR patients is a major milestone in Intellia’s mission to develop medicines to cure severe and life-threatening diseases,” said Intellia’s president and chief John Leonard, M.D.

“Our trial is the first step toward demonstrating that our therapeutic approach could have a permanent effect, potentially halting and reversing all forms of ATTR. Once we have established safety and the optimal dose, our goal is to expand this study and rapidly move to pivotal studies, in which we aim to enroll both polyneuropathy and cardiomyopathy patients.”

SOURCE

https://www.fiercebiotech.com/biotech/intellia-to-kickstart-first-single-course-curative-crispr-shot-as-it-hopes-to-beat-rivals

Other related articles published in this Open Access Online Scientific Journal include the following:

 

Familial transthyretin amyloid polyneuropathy

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/06/10/familial-transthyretin-amyloid-polyneuropathy/

 

Stabilizers that prevent transthyretin-mediated cardiomyocyte amyloidotic toxicity

Reporter and curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/12/02/stabilizers-that-prevent-transthyretin-mediated-cardiomyocyte-amyloidotic-toxicity/

 

Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/10/29/transthyretin-amyloid-cardiomyopathy-attr-cm-u-s-fda-approves-vyndaqel-and-vyndamax-for-this-rare-and-fatal-disease/

 

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/13/alnylam-announces-first-ever-fda-approval-of-an-rnai-therapeutic-onpattro-patisiran-for-the-treatment-of-the-polyneuropathy-of-hereditary-transthyretin-mediated-amyloidosis-in-adults/

 

 

Read Full Post »

Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

 

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

 

UPDATED on 8/9/2020

 

UPDATED on 3/11/2020

Coronaviruses

According to the World Health Organization, coronaviruses make up a large family of viruses named for the crown-like spikes found on their surface (Figure 1). They carry their genetic material in single strands of RNA and cause respiratory problems and fever. Like HIV, coronaviruses can be transmitted between animals and humans.  Coronaviruses have been responsible for the Severe Acute Respiratory Syndrome (SARS) pandemic in the early 2000s and the Middle East Respiratory Syndrome (MERS) outbreak in South Korea in 2015. While the most recent coronavirus, COVID-19, has caused international concern, accessible and inexpensive sequencing is helping us understand COVID-19 and respond to the outbreak quickly.

Figure 1. Coronaviruses with the characteristic spikes as seen under a microscope.

First studies that explore genetic susceptibility to COVID-19 are now being published. The first results indicate that COVID-19 infects cells using the ACE2 cell-surface receptor. Genetic variants in the ACE2 receptor gene are thus likely to influence how effectively COVID-19 can enter the cells in our bodies. Researchers hope to discover genetic variants that confer resistance to a COVID-19 infection, similar to how some variants in the CCR5 receptor gene make people immune to HIV. At Nebula Genomics, we are monitoring the latest COVID-19 research and will add any relevant discoveries to the Nebula Research Library in a timely manner.

The Role of Genomics in Responding to COVID-19

Scientists in China sequenced COVID-19’s genome just a few weeks after the first case was reported in Wuhan. This stands in contrast to SARS, which was discovered in late 2002 but was not sequenced until April of 2003. It is through inexpensive genome-sequencing that many scientists across the globe are learning and sharing information about COVID-19, allowing us to track the evolution of COVID-19 in real-time. Ultimately, sequencing can help remove the fear of the unknown and allow scientists and health professionals to prepare to combat the spread of COVID-19.

Next-generation DNA sequencing technology has enabled us to understand COVID-19 is ~30,000 bases long. Moreover, researchers in China determined that COVID-19 is also almost identical to a coronavirus found in bats and is very similar to SARS. These insights have been critical in aiding in the development of diagnostics and vaccines. For example, the Centers for Disease Control and Prevention developed a diagnostic test to detect COVID-19 RNA from nose or mouth swabs.

Moreover, a number of different government agencies and pharmaceutical companies are in the process of developing COVID-19 vaccines to stop the COVID-19 from infecting more people. To protect humans from infection inactivated virus particles or parts of the virus (e.g. viral proteins) can be injected into humans. The immune system will recognize the inactivated virus as foreign, priming the body to build immunity against possible future infection. Of note, Moderna Inc., the National Institute of Allergy and Infectious Diseases, and Coalition for Epidemic Preparedness Innovations identified a COVID-19 vaccine candidate in a record 42 days. This vaccine will be tested in human clinical trials starting in April.

For more information about COVID-19, please refer to the World Health Organization website.

SOURCE

https://blog.nebula.org/role-of-genomics-coronavirus-covid-19/?utm_source=Nebula%20Genomics&utm_medium=email&utm_campaign=COVID-19

Aviva Lev-Ari
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Aviva Lev-Ari
@AVIVA1950

My BIO lnkd.in/eEyn69r MediaPharma ex-SRI ex-MITRE ex-McGraw-Hill Followed by

Aviva Lev-Ari
@AVIVA1950

Predicting the #ProteinStructure of #Coronavirus: #Inhibition of #Nsp15 #Cryo-EM – #spike #protein structure (#experimentally verified) vs #AI-predicted protein structures (not verified) of

(

) #AlphaFold

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Eric Topol
@EricTopol
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The problem w/ visionaries is that we don’t recognize them in a timely manner (too late) Ralph Baric @UNCpublichealth and Vineet Menachery deserve recognition for being 5 yrs ahead of #COVID19 nature.com/articles/nm.39 @NatureMedicine pnas.org/content/113/11 @PNASNews via @hoondy

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Senior, A.W., Evans, R., Jumper, J. et al. Improved protein structure prediction using potentials from deep learningNature 577, 706–710 (2020)https://doi.org/10.1038/s41586-019-1923-7

Abstract

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)—a blind assessment of the state of the field—AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7. https://doi.org/10.1038/s41586-019-1923-7

[ALA added bold face]

COVID-19 outbreak

The scientific community has galvanised in response to the recent COVID-19 outbreak, building on decades of basic research characterising this virus family. Labs at the forefront of the outbreak response shared genomes of the virus in open access databases, which enabled researchers to rapidly develop tests for this novel pathogen. Other labs have shared experimentally-determined and computationally-predicted structures of some of the viral proteins, and still others have shared epidemiological data. We hope to contribute to the scientific effort using the latest version of our AlphaFold system by releasing structure predictions of several under-studied proteins associated with SARS-CoV-2, the virus that causes COVID-19. We emphasise that these structure predictions have not been experimentally verified, but hope they may contribute to the scientific community’s interrogation of how the virus functions, and serve as a hypothesis generation platform for future experimental work in developing therapeutics. We’re indebted to the work of many other labs: this work wouldn’t be possible without the efforts of researchers across the globe who have responded to the COVID-19 outbreak with incredible agility.

Knowing a protein’s structure provides an important resource for understanding how it functions, but experiments to determine the structure can take months or longer, and some prove to be intractable. For this reason, researchers have been developing computational methods to predict protein structure from the amino acid sequence.  In cases where the structure of a similar protein has already been experimentally determined, algorithms based on “template modelling” are able to provide accurate predictions of the protein structure. AlphaFold, our recently published deep learning system, focuses on predicting protein structure accurately when no structures of similar proteins are available, called “free modelling”.  We’ve continued to improve these methods since that publication and want to provide the most useful predictions, so we’re sharing predicted structures for some of the proteins in SARS-CoV-2 generated using our newly-developed methods.

It’s important to note that our structure prediction system is still in development and we can’t be certain of the accuracy of the structures we are providing, although we are confident that the system is more accurate than our earlier CASP13 system. We confirmed that our system provided an accurate prediction for the experimentally determined SARS-CoV-2 spike protein structure shared in the Protein Data Bank, and this gave us confidence that our model predictions on other proteins may be useful. We recently shared our results with several colleagues at the Francis Crick Institute in the UK, including structural biologists and virologists, who encouraged us to release our structures to the general scientific community now. Our models include per-residue confidence scores to help indicate which parts of the structure are more likely to be correct. We have only provided predictions for proteins which lack suitable templates or are otherwise difficult for template modeling.  While these understudied proteins are not the main focus of current therapeutic efforts, they may add to researchers’ understanding of SARS-CoV-2.

Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them.

Interested researchers can download the structures here, and can read more technical details about these predictions in a document included with the data. The protein structure predictions we’re releasing are for SARS-CoV-2 membrane protein, protein 3a, Nsp2, Nsp4, Nsp6, and Papain-like proteinase (C terminal domain). To emphasise, these are predicted structures which have not been experimentally verified. Work on the system continues for us, and we hope to share more about it in due course.

Citation:  John Jumper, Kathryn Tunyasuvunakool, Pushmeet Kohli, Demis Hassabis, and the AlphaFold Team, “Computational predictions of protein structures associated with COVID-19”, DeepMind website, 5 March 2020, https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

SARS-COV-2 MEMBRANE PROTEIN: A RENDERING OF ONE OF OUR PROTEIN STRUCTURE PREDICTIONS

SOURCES

Computational predictions of protein structures associated with COVID-19

https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

AlphaFold: Using AI for scientific discovery 

https://deepmind.com/blog/article/AlphaFold-Using-AI-for-scientific-discovery

 

DeepMind has shared its results with researchers at the Francis Crick Institute, a biomedical research lab in the UK, as well as offering it for download from its website.

“Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them,” it said. [ALA added bold face]

There are 93,090 cases of COVID-19, and 3,198 deaths, spread across 76 countries, according to the latest report from the World Health Organization at time of writing. ®

SOURCE

https://www.theregister.co.uk/2020/03/06/deepmind_covid19_outbreak/

 

  • MHC content – The spike protein is thought to be the key to binding to cells via the angiotensin II receptor, the major mechanism the immune system uses to distinguish self from non-self

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Syed Faraz Ahmed 1,† , Ahmed A. Quadeer 1, *,† and Matthew R. McKay 1,2, *

1 Department of Electronic and Computer Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China; sfahmed@connect.ust.hk

2 Department of Chemical and Biological Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China

* Correspondence: eeaaquadeer@ust.hk.com (A.A.Q.); m.mckay@ust.hk (M.R.M.)

These authors contributed equally to this work.

Received: 9 February 2020; Accepted: 24 February 2020; Published: 25 February 2020

Abstract:

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.

Keywords: Coronavirus; 2019-nCoV; 2019 novel coronavirus; SARS-CoV-2; COVID-19; SARS-CoV; MERS-CoV; T cell epitopes; B cell epitopes; vaccine [ALA added bold face]

SOURCE

https://www.mdpi.com/1999-4915/12/3/254/pdf

 

Selected Online COMMENTS to

https://forums.theregister.co.uk/forum/all/2020/03/06/deepmind_covid19_outbreak/

MuscleguySilver badge

Re: Protein structure prediction has been done for ages…

Not quite, Natural Selection does not measure methods, it measures outputs, usually at the organism level.

Sure correct folding is necessary for much protein function and we have prions and chaperone proteins to get it wrong and right.

The only way NS measures methods and mechanisms is if they are very energetically wasteful. But there are some very wasteful ones out there. Beta-Catenin at the end of point of Wnt signalling comes particularly to mind.

Chemist

Re: Does not matter at all

“Determining the structure of the virus proteins might also help in developing a molecule that disrupts the operation of just those proteins, and not anything else in the human body.”

Well it might, but predicting whether a ‘drug’ will NOT interact with any other of the 20000+ protein in complex organisms is well beyond current science. If we could do that we could predict/avoid toxicity and other non-mechanism related side-effects & mostly we can’t.

rob miller

Title

There are 480 structures on PDBe resulting from a search on ‘coronavirus,’ the top hits from MERS and SARS. PR stunt or not, they did win the most recent CASP ‘competition’, so arguably it’s probably our best shot right now – and I am certainly not satisfied that they have been sufficiently open in explaining their algorithms though I have not checked in the last few months. No one is betting anyone’s health on this, and it is not like making one wrong turn in a series of car directions. Latest prediction algorithms incorporate contact map predictions, so it’s not like a wrong dihedral angle sends the chain off in the wrong direction. A decent model would give something to run docking algorithms against with a series of already approved drugs, then we take that shortlist into the lab. A confirmed hit could be an instantly available treatment, no two year wait as currently estimated. [ALA added bold face]

jelabarre59Silver badge

Re: these structure predictions have not been experimentally verified

Naaaah. Can’t possibly be a stupid marketing stunt.

Well yes, a good possibility. But it can also be trying to build on the open-source model of putting it out there for others to build and improve upon. Essentially opening that “peer review” to a larger audience quicker. [ALA added bold face]

We shall see.

Anonymous Coward

Anonymous CowardWhat bothers me, besides the obvious PR stunt, is that they say this prediction is licensed. How can a prediction from software be protected by, I presume, patents? And if this can be protected without even verifying which predictions actually work, what’s to stop someone spitting out millions of random, untested predictions just in case they can claim ownership later when one of them is proven to work? [ALA added bold face]

 

 

SOURCES

 

  • AI-predicted protein structures could unlock vaccine for Wuhan coronavirus… if correct… after clinical trials It’s not quite DeepMind’s ‘Come with me if you want to live’ moment, but it’s close, maybe

Experimentally derived by a group of scientists at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases, an agency under the US National Institute of Health. They both feature a “Spike protein structure.”

  • Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

See all authors and affiliations

Science  19 Feb 2020:
eabb2507
DOI: 10.1126/science.abb2507

 

  • Israeli scientists: We have developed a coronavirus vaccine

https://www.fromthegrapevine.com/health/coronavirus-vaccine-israel-migal-research-institute-david-zigdon

Other related articles published in this Open Access Online Scientific Journal include the following:

 

  • Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

 

  • Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled Curator:

Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/03/06/is-it-time-for-the-virtual-scientific-conference-coronavirus-travel-restrictions-conferences-cancelled/

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Healing Powers of Fibrinogen

Reporter: Irina Robu, PhD

Recent research from University of Alberta is looking at the role of fibrinogen, the substrate of thrombin in regulating a natural defense mechanism in the body. Fibrinogen is a well-known protein that is essential for wound healing and blood clotting in the body. Levels of fibrinogen increase in inflammatory states as part of the acute-phase response.

However, daily variation in plasma fibrinogen levels weakens its potential as a biomarker of cardiovascular risk. The discovery is expected to contribute to enhanced diagnosis and treatments for patients in a variety of diseases ranging from inflammation, to heart failure, to cancer.

Yet, a study published in Scientific Reports in March 2019 show that fibrinogen can also be a natural inhibitor of an enzyme named MMP2, which is important for normal organ development and repair. The researchers believe an essential function of fibrinogen is to allow or disallow the enzyme to carry out its normal functions. Nevertheless, high levels of fibrinogen may disproportionately inhibit MMP2, that could result in arthritic and cardiac disorders.

The researcher highlights the inner workings of the MMP family of enzymes by having a greater understanding of how MMPs are regulated. They hypothesize that abnormal MMP2 activity could be an unwelcome side effect of common medications such as the cholesterol-lowering drugs and the antibiotic doxycycline, both of which are known to inhibit MMPs. They also emphasize that future therapeutic developments must strike a balance between the levels of MMPs and their inhibitors, such as fibrinogen, so that net MMP activity in the body remains at nearly normal levels.

SOURCE

https://www.technologynetworks.com/biopharma/news/healing-protein-also-hinders-320533?utm_campaign=NEWSLETTER_TN_Breaking%20Science%20News

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The Journey of Antibiotic Discovery

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The term ‘antibiotic’ was introduced by Selman Waksman as any small molecule, produced by a microbe, with antagonistic properties on the growth of other microbes. An antibiotic interferes with bacterial survival via a specific mode of action but more importantly, at therapeutic concentrations, it is sufficiently potent to be effective against infection and simultaneously presents minimal toxicity. Infectious diseases have been a challenge throughout the ages. From 1347 to 1350, approximately one-third of Europe’s population perished to Bubonic plague. Advances in sanitary and hygienic conditions sufficed to control further plague outbreaks. However, these persisted as a recurrent public health issue. Likewise, infectious diseases in general remained the leading cause of death up to the early 1900s. The mortality rate shrunk after the commercialization of antibiotics, which given their impact on the fate of mankind, were regarded as a ‘medical miracle’. Moreover, the non-therapeutic application of antibiotics has also greatly affected humanity, for instance those used as livestock growth promoters to increase food production after World War II.

 

Currently, more than 2 million North Americans acquire infections associated with antibiotic resistance every year, resulting in 23,000 deaths. In Europe, nearly 700 thousand cases of antibiotic-resistant infections directly develop into over 33,000 deaths yearly, with an estimated cost over €1.5 billion. Despite a 36% increase in human use of antibiotics from 2000 to 2010, approximately 20% of deaths worldwide are related to infectious diseases today. Future perspectives are no brighter, for instance, a government commissioned study in the United Kingdom estimated 10 million deaths per year from antibiotic resistant infections by 2050.

 

The increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures – platforms – that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines.

 

The increase in drug-resistant pathogens is a consequence of multiple factors, including but not limited to high rates of antimicrobial prescriptions, antibiotic mismanagement in the form of self-medication or interruption of therapy, and large-scale antibiotic use as growth promotors in livestock farming. For example, 60% of the antibiotics sold to the USA food industry are also used as therapeutics in humans. To further complicate matters, it is estimated that $200 million is required for a molecule to reach commercialization, with the risk of antimicrobial resistance rapidly developing, crippling its clinical application, or on the opposing end, a new antibiotic might be so effective it is only used as a last resort therapeutic, thus not widely commercialized.

 

Besides a more efficient management of antibiotic use, there is a pressing need for new platforms capable of consistently and efficiently delivering new lead substances, which should attend their precursors impressively low rates of success, in today’s increasing drug resistance scenario. Antibiotic Discovery Platforms are aiming to screen large libraries, for instance the reservoir of untapped natural products, which is likely the next antibiotic ‘gold mine’. There is a void between phenotanypic screening (high-throughput) and omics-centered assays (high-information), where some mechanistic and molecular information complements antimicrobial activity, without the laborious and extensive application of various omics assays. The increasing need for antibiotics drives the relentless and continuous research on the foreground of antibiotic discovery. This is likely to expand our knowledge on the biological events underlying infectious diseases and, hopefully, result in better therapeutics that can swing the war on infectious diseases back in our favor.

 

During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

 

References:

 

https://www.mdpi.com/2079-6382/8/2/45/htm

 

https://www.ncbi.nlm.nih.gov/pubmed/19515346

 

https://www.ajicjournal.org/article/S0196-6553(11)00184-2/fulltext

 

https://www.ncbi.nlm.nih.gov/pubmed/21700626

 

http://www.med.or.jp/english/journal/pdf/2009_02/103_108.pdf

 

Read Full Post »

Pancreatic cancer survival is determined by ratio of two enzymes, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

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Changes in Levels of Sex Hormones and N-Terminal Pro–B-Type Natriuretic Peptide as Biomarker for Cardiovascular Diseases

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Considerable differences exist in the prevalence and manifestation of atherosclerotic cardiovascular disease (CVD) and heart failure (HF) between men and women. Premenopausal women have a lower risk of CVD and HF compared with men; however, this risk increases after menopause. Sex hormones, particularly androgens, are associated with CVD risk factors and events and have been postulated to mediate the observed sex differences in CVD.

 

B-type natriuretic peptides (BNPs) are secreted from cardiomyocytes in response to myocardial wall stress. BNP plays an important role in cardiovascular remodelling and volume homeostasis. It exerts numerous cardioprotective effects by promoting vasodilation, natriuresis, and ventricular relaxation and by antagonizing fibrosis and the effects of the renin-angiotensin-aldosterone system. Although the physiological role of BNP is cardioprotective, pathologically elevated N-terminal pro–BNP (NT-proBNP) levels are used clinically to indicate left ventricular hypertrophy, dysfunction, and myocardial ischemia. Higher NT-proBNP levels among individuals free of clinical CVD are associated with an increased risk of incident CVD, HF, and cardiovascular mortality.

 

BNP and NT-proBNP levels are higher in women than men in the general population. Several studies have proposed the use of sex- and age-specific reference ranges for BNP and NT-proBNP levels, in which reference limits are higher for women and older individuals. The etiology behind this sex difference has not been fully elucidated, but prior studies have demonstrated an association between sex hormones and NT-proBNP levels. Recent studies measuring endogenous sex hormones have suggested that androgens may play a larger role in BNP regulation by inhibiting its production.

 

Data were collected from a large, multiethnic community-based cohort of individuals free of CVD and HF at baseline to analyze both the cross-sectional and longitudinal associations between sex hormones [total testosterone (T), bioavailable T, freeT, dehydroepiandrosterone (DHEA), SHBG, and estradiol] and NT-proBNP, separately for women and men. It was found that a more androgenic pattern of sex hormones was independently associated with lower NT-proBNP levels in cross-sectional analyses in men and postmenopausal women.

 

This association may help explain sex differences in the distribution of NT-proBNP and may contribute to the NP deficiency in men relative to women. In longitudinal analyses, a more androgenic pattern of sex hormones was associated with a greater increase in NT-proBNP levels in both sexes, with a more robust association among women. This relationship may reflect a mechanism for the increased risk of CVD and HF seen in women after menopause.

 

Additional research is needed to further explore whether longitudinal changes in NT-proBNP levels seen in our study are correlated with longitudinal changes in sex hormones. The impact of menopause on changes in NT-proBNP levels over time should also be explored. Furthermore, future studies should aim to determine whether sex hormones directly play a role in biological pathways of BNP synthesis and clearance in a causal fashion. Lastly, the dual role of NTproBNP as both

  • a cardioprotective hormone and
  • a biomarker of CVD and HF, as well as
  • the role of sex hormones in delineating these processes,

should be further explored. This would provide a step toward improved clinical CVD risk stratification and prognostication based on

  • sex hormone and
  • NT-proBNP levels.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/76480?xid=NL_CardioEndoConnection_2018-12-27

 

https://www.ncbi.nlm.nih.gov/pubmed/30137406

 

https://www.ncbi.nlm.nih.gov/pubmed/22064958

 

https://www.ncbi.nlm.nih.gov/pubmed/24036936

 

https://www.ncbi.nlm.nih.gov/pubmed/19854731

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Once herpes simplex infects a person, the virus goes into hiding inside nerve cells, hibernating there for life, periodically waking up from its sleep to reignite infection, causing cold sores or genital lesions to recur. Research from Harvard Medical School showed that the virus uses a host protein called CTCF, or cellular CCCTC-binding factor, to display this type of behavior. Researchers revealed with experiments on mice that CTCF helps herpes simplex regulate its own sleep-wake cycle, enabling the virus to establish latent infections in the body’s sensory neurons where it remains dormant until reactivated. Preventing that latency-regulating protein from binding to the virus’s DNA, weakened the virus’s ability to come out of hiding.

 

Herpes simplex virus’s ability to go in and out of hiding is a key survival strategy that ensures its propagation from one host to the next. Such symptom-free latency allows the virus to remain out of the reach of the immune system most of the time, while its periodic reactivation ensures that it can continue to spread from one person to the next. On one hand, so-called latency-associated transcript genes, or LAT genes, turn off the transcription of viral RNA, inducing the virus to go into hibernation, or latency. On the other hand, a protein made by a gene called ICP0 promotes the activity of genes that stimulate viral replication and causes active infection.

 

Based on these earlier findings, the new study revealed that this balancing act is enabled by the CTCF protein when it binds to the viral DNA. Present during latent or dormant infections, CTCF is lost during active, symptomatic infections. The researchers created an altered version of the virus that lacked two of the CTCF binding sites. The absence of the binding sites made no difference in early-stage or acute infections. Similar results were found in infected cultured human nerve cells (trigeminal ganglia) and infected mice model. The researchers concluded that the mutant virus was found to have significantly weakened reactivation capacity.

 

Taken together, the experiments showed that deleting the CTCF binding sites weakened the virus’s ability to wake up from its dormant state thereby establishing the evidence that the CTCF protein is a key regulator of sleep-wake cycle in herpes simplex infections.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29437926

 

https://hms.harvard.edu/news/viral-hideout?utm_source=Silverpop

 

https://www.ncbi.nlm.nih.gov/pubmed/30110885

 

https://www.ncbi.nlm.nih.gov/pubmed/30014861

 

https://www.ncbi.nlm.nih.gov/pubmed/18264117

 

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