Structural chemistry and therapeutic intervention of protein-protein interactions in immune response, human immunodeficiency virus entry, and apoptosis

Protein-protein interactions involved in diverse biological functions are largely unexplored therapeutic targets, and present a major challenge and opportunity for drug design research. Encouraging new approaches to this problem recently have emerged from studies of small molecule regulators of protein-protein complexes. This review outlines the basic concepts for two of these approaches, based on structural and chemical strategies, by illustrating their application in the design of small molecule inhibitors for three biological systems: (1) cell surface molecules CD4 and CD8 involved in immune response, (2) chemokine receptor-ligand interactions implicated in human immunodeficiency virus entry, and (3) B-cell leukemia/lymphoma-2 family proteins essential for regulation of programmed cell death or apoptosis. The design and discovery of these novel reagents provide valuable tools to probe fundamental questions about a particular protein-protein complex, and may lead to a new generation of potential therapeutic agents. Furthermore, these studies suggest a framework for chemical intervention of other protein-protein interactions involved in many pathological processes.