Open Competition 3 - Biotechnology
Novel Technology for the Discovery of D-Peptide Therapeutics for Cytokine-Mediated Diseases
Develop an approach for discovering D-peptide drugs, a new class of therapeutics likely to be pharmacologically superior to monoclonal antibody drugs and less immunogenic.
Sponsor: Cosmix Therapeutics (formerly Gryphon Therapeutics)250 E. Grand Avenue
South San Francisco, CA 94080
In this three-year project, Gryphon Therapeutics is developing a new class of drugs based on peptides composed of D-amino acids. These D-peptide therapeutics (DRXs) may be pharmacologically superior to currently-used therapeutic peptides composed of naturally occurring L-amino acids. L-peptides are often quickly destroyed by proteolytic enzymes, and may elicit an immune response that renders them ineffective or even toxic. DRXs are not prone to proteolytic enzyme destruction and are less immunogenic. Gryphon will chemically synthesize a D-protein target for screening against biological L-peptide libraries. This combinatorial biological approach should enable the identification of ligands that bind tightly to the D-target. The DRX, the mirror image of the L-peptide binders, will then be made by copying its sequence using D-amino acids. The resulting D-peptides that bind tightly to the natural L-protein target will be selected as therapeutic candidates. A DRX specific for tumor necrosis factor alpha (TNF-alpha), a validated L-protein target in the treatment of chronic inflammatory conditions, will be the first demonstration of this approach. After testing DRX candidates in cells and animals, promising molecules will be manufactured for preclinical trials. Screening, synthesizing, testing, and analyzing DRX peptides may require assistance from several subcontractors: Cosmix (Braunschweig, Germany); C.S. Bio (San Carlos, CA); Phylos, Inc. (Lexington, MA); the University of Michigan (Ann Arbor, MI); the University of California at Davis (Davis, CA); CAT GmbH & Co. (Tubingen, Germany); Washington State University (Pullman, WA); and Northview Pacific Labs (Hercules, CA). Using Gryphon's proprietary technology to synthesize correctly folded D-TNF, which is too large for conventional solid-phase peptide synthesis, presents a substantial risk. Another risk is that the D-peptides finally selected may not bind tightly enough to L-TNF to be effective therapeutics. Private investors deem this project well outside of the risk profile for Gryphon's portfolio. ATP funding is needed if this innovative, high-risk project for developing D-peptide therapeutics is to proceed. Using DRXs rather than monoclonal antibodies to treat diseases offers notable advantages. The smaller size and greater stability of the molecules should make them easier to formulate than monoclonal antibodies. DRXs are expected to be less immunogenic and resistant to enzymatic degradation. Initially, anti-TNF DRXs could lead to better treatments for rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Ultimately, the final DRX peptides may yield reduced manufacturing costs, thereby saving consumers money.