Synthesis of compounds with peptide characteristics

Although peptides have shown some promise in clinical trials as therapeutic agents, its success has largely been limited by several factors, including rapid degradation by peptidases, poor cell permeability, and a lack of binding specificity resulting from conformational inflexibility. Over the years research has overcome some of these limitations with peptidomimetics-a system for the production of modified chemical compounds capable of mimicking the structural and or functional properties of peptides. In most cases, peptidomimetic compounds are prepared one at a time. A few researchers have attempted to design combinatorial strategies to generate peptidomimetic libraries, but these methods are limited by lack of stereochemical complexity and a restricted ability to substitute base molecules. Also, a fixed structure to mimic the peptide bond does not allow subsequent modification and diversification of the structure. As a consequence, there is a particular need for synthetic strategies capable of producing complex, highly diversified libraries of compounds that act as peptidominetics. There is also a high-demand for methods and compounds that allow significant stereochemical control and functional group diversity in the production of such libraries.

The laboratory of Professor Gregory Verdine had developed a novel modular synthetic mechanism for preparing and screening libraries of peptidomimetics with all possible stereoisomers. The platform includes a semirigid acyclic framework (cis-enediol unit), which, from the standpoint of biological potency, is especially important for proper discovery of lead compounds. This framework is rich in stereoisogenic centers with a hydrocarbon framework presenting both hydrogen-bonding functionality and variable side-chain ("R") groups. Most importantly, the compounds resulting from this system retain the desired functional and/or structural aspects of natural, wild type peptides.


In contrast to current methods for design and synthesis of small molecule libraries that focus exclusively on achieving diversity through functional group variation, this novel platform technology offers diversification through extensive stereochemical diversification. The small molecule libraries have exhaustive variation at every sp3-hybridized center. The system is not limited to the synthesis of libraries of peptide mimics-encompasses the broader concept of providing any collection (peptidomimetics and non-peptidomimetics) of chemical compounds having stereodiversity. The monomers can also be obtained in high yield.

Libraries of compounds generated from the synthetic platform are to be screened for their biological efficacy and lead compounds are to be formulated and utilized as therapeutic pharmaceuticals for treatment and prevention of disease. More particularly, peptide therapies are heavily invested in the treatment of autoimmune diseases.

Intellectual Property Status: Patent(s) Pending