The overall goal of this project is to optimize the inherent cytotoxicity, antiviral, and immunomodulatory activity of the didemnins and eventually develop new drugs for the treatment of cancer, viral infections, and immune disorders. In Phase I, a new solid-phase synthesis of didemnin A and a new method for the cyclization-cleavage of this compound from the solid support will be developed. This methodology will then be used to synthesize a small cyclodepsipeptide library. Eventually, these combinatorial chemistry techniques will be utilized to generate large diverse libraries of cyclodepsipeptides which will be screened for useful bioactivity. beads which are identified in these screens will be used to design subsequent focused libraries, so as to further optimize useful bioactivity. Suitable candidates would undergo further testing and development in collaboration with a pharmaceutical partner.
New therapies to treat cancer, viral infections, and immune disorders are urgently needed. Didemnins represent valuable leads in each of these disease categories. The proposed technology would greatly facilitate the search for active compounds structurally related to the didemnins. In addition, the methods being developed should be applicable to other cyclic peptides and depsipeptides of varying ring size and sequence for the identification of drugs for other diseases.
