A new class of inhibitors targeting protein-protein interactions: Oligooxopiperazines as non-peptidic α-helix mimetics
Associate Professor, Department of Chemistry
Background and Description of Technology:
Development of small molecules inhibitors targeting protein-protein interactions (PPIs) is extremely challenging. A fundamental limitation lies in the inability of traditional pharmaceuticals to target spatially extended protein interfaces. Proteins tend to interact with their partners via folded sub-domains in which the backbone possesses secondary structure. α-Helices are the most prevalent secondary structures and are involved in numerous PPIs, many of which play key roles in pathways in cancer, autoimmunity, cardiovascular, CNS, metabolic and infectious disease. Small molecules that can mimic this conformation will be invaluable as ligands for proteins and nucleic acid receptors and as inhibitors for critical PPIs, consequently providing vast opportunities for drug discovery for otherwise “undruggable” targets.
Dr. Arora is utilizing oxopiperazines oligomers (oligooxopiperazines) as non-peptidic scaffolds for designing α-helix mimetics. The piperazine skeletonʼs favorable drug properties underscores its wide use in drug discovery and evidenced by the scores of piperazine derivatives in notable successful drugs. Using computational studies, Dr. Arora observed that oligooxopiperazines have predicted stable, helical and strand structures due to the conformational constraints inherent in the system. NMR, circular dichroism and molecular modeling provide compelling evidence that this class of compounds adopts stable conformations that reproduce arrangements of α-helix residues involved in binding other proteins. Hence, this technology allows for the rapid design and synthesis of a library of compounds tailored to the exact interface of specific PPIs, facilitating screening for lead hits with known mechanism of actions.
Patent applications have been filed covering the compounds and methods of synthesis and use. NYU is seeking a commercial partner to focus on developing this drug discovery platform to identify new lead compounds targeting α-helical protein-protein interactions.