English: Schematic sketch showing the transport types at the blood-brain barrier. Deutsch: Schematische Darstellung der Transportmechanismen an der Blut-Hirn-Schranke. Français : Schéma des types de transport à travers la barrière hémato-encéphalique (Photo credit: Wikipedia)
Larry H Bernstein, MD
Reporter
Provided without comment. Quite interesting.
novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor
Description
A Catalan Research Institute based in Barcelona (Spain) has identified novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor. These shuttles are a powerful alternative to carry a wide variety of small and large molecules as cargos. This represents a novel opportunity to develop new delivery carriers able to cross actively a range of biological barriers.
New and innovative aspects
These compounds are novel drug delivery carriers that provide a non-invasive, non-antigenic, stable and receptor-specific way to transport drugs across the Blood-Brain Barrier and into the Central Nervous System.
These compounds show high permeability, biocompatibility, good solubility in water and resistance to proteases.
Specifications
The treatment of most neurological disorders has not been fully addressed mainly because of the neuroprotective role of the blood-brain barrier (BBB) that hinders the delivery of many diagnostic and therapeutic agents into the brain. Consequently, therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts: 98% of compounds smaller than 400Da and 100% of larger ones do not reach further drug development stages.
Most central nervous system (CNS) diseases, however, are complex disorders with difficult molecular targets that require larger, safer and more selective drugs. As a result, brain tumors, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and central nervous system (CNS) diseases such as schizophrenia are not successfully treated. Therefore, finding an efficient CNS delivery system is one of the major challenges in neurological treatment and one our technology can potentially overcome.
One of the best approaches for drug delivery to the brain is the use of endogenous transport mechanisms, such as receptor-mediated transcystosis. Peptides are biocompatible molecules able to transport cargos (i.e. therapeutic compounds) to specific tissues such as the brain. However, one of the main limitations of peptides as therapeutic agents is their low stability in plasma.
The use of non-natural amino acids in peptidic sequences can circumvent this problem because they are resistant to human serum proteases. Using this approach, we obtained several modified peptides. Two of them were selected based on their protease resistance and transport capacity across the blood-brain barrier, using a specific endogenous receptor. Both peptides showed enhanced membrane permeability in vitro in comparison to standard peptides and even greater stability in plasma (over 24h).
Main advantages of its use
Novel delivery technology that provides a non-invasive, non-antigenic, permeable, stable, soluble and receptor-specific way to transport drugs across the BBB and into the CNS.
This technology may ultimately allow the delivery of therapeutic agents, even large ones, across the BBB and other biological barriers, thus increasing the effectiveness of existing or new drugs.
Potential of application in a wide number of fields and in transport through various biological barriers.
Applications
Biotechnological and Pharmaceutical companies specialized in drug discovery, drug delivery, neurological disorders, tools to cross the Blood-brain barrier. The final aim is to increase the efficiency of existing molecules for the treatment of neurological disorders.
Molecule and treatment design, drug manufacture, treatment of neurological disorders, drug delivery across the blood-brain barrier (BBB).
Intellectual property status
This invention is protected by a priority application in Spain and we plan to apply for a PCT in due time.
Related articles
- Barrier (BBB) issue from a biological and pathological perspective (tginnovations.wordpress.com)
- McGill University Researchers Create Novel Nanoparticles That can Bypass Blood-Brain Barrier (nsti.org)
- Repairing Brain Damage, A Significant Departure From Current Alzheimer’s Treatments (medicalnewstoday.com)
- Mechanisms And Clinical Implications For Parkinson’s, Schizophrenia, And Other Diseases (medicalnewstoday.com)
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.