In the laboratory of Prof. Amnon Albeck of the Department of Chemistry, a variety of projects are underway in the field of drug discovery and development.
One of these involves the development of novel computer-assisted drug design (CADD) tools to assist medicinal chemists and the pharmaceutical industry in the design of new bioactive compounds. Others address specific therapeutic targets that could be further developed into useful drugs.
These projects involve the design and synthesis of enzyme inhibitors as well as evaluation of their activity at various levels, from in-vitro studies to in-vivo animal model experiments.
In research that may help clinicians overcome the problem of mutational drug resistance, Prof. Albeck, in conjunction with Prof. Michael Shokhen, is developing computational tools for the design of new antibacterial and antiviral drugs based on enzyme inhibitors. Common drug design tools deal with non-covalent inhibitors, which eventually suffer from mutational drug resistance.
The emergence of resistant bacterial and viral strains, as well as cancer cells, has become a major problem in modern medicine. The methodology developed by Albeck’s group can treat transition-state analog inhibitors. These reversible covalent inhibitors interact directly with the catalytic machinery of the enzyme, which is not subject to mutations. While the common CADD tools are either structure-based or ligand / pharmacophore-based methodologies, Albeck’s approach can be classified as a mechanism-based drug design tool.
Understanding the mode of action of enzymes at the molecular level has important potential applications, as it opens up possibilities to selectively control or modulate such activities. This approach is essential for basic research, as well as for the development of new drugs and other biologically active compounds.
Albeck and his team study proteolytic enzymes, using biochemical techniques (protein purification and characterization, enzymatic kinetics), chemical methods (synthesis, NMR studies, X-ray crystallography) and computational biochemistry. They also study proteolytic enzyme inhibitors, addressing both mechanistic and applied objectives.
Peptide analogs, in which one or more functionalities have been altered, are promising for many applications in drug development, diagnostics, and mechanistic studies. Albeck’s lab develops innovative methods for the preparation of such peptide analogs, applying them for the synthesis of novel enzyme inhibitors.
These inhibitors may serve mechanistic research goals, or may be developed for drug discovery projects. Their functional alterations may include the introduction of reactive functional groups to covalently interact with a target enzyme, or conversion of a peptide bond to a metabolically stable isostere. Peptido-mimetics-based inhibitors are synthesized using non-peptidic templates. In these new compounds, critical peptidic functional groups are added in specific spatial positions, resulting in optimal interactions with the target enzyme.
As a research group that combines both experimental and computational research tools, Albeck’s lab is committed to the improvement and further development of its drug design computational methodologies and their application in practical drug development projects. Ongoing projects target bacterial and viral infectious diseases, necrotic cell death, and neurodegenerative diseases.