Inhibition of Protein-Protein Association by Small Molecules: Approaches and Progress

摘要

The ability of proteins to associate rests at the core of biology. Cellular architecture, information transfer, and chemical specificity rely upon highly precise recognition events; frequently these events involve the assembly of two or more proteins. The binding of two proteins may occur with low or high affinity, but clearly protein association in cells does not occur in a random, disorganized way. Rather, protein association is carefully scripted to achieve specific goals, be they the assembly of particular subcellular architectures or the relay of information (signal transduction). Protein-protein association events may be recognized in all aspects of cell biochemistry. The mammalian immune response relies in large part upon the recognition of proteins and peptides by antibodies. Cell-cell recognition and attachment to the extracellular matrix is mediated by cell surface receptors (cadherins and integrins) that are ligated by protein partners such as actin and fibronection. Signal transduction from the cell surface to the nucleus is frequently mediated by one or more protein-protein associations, e.g., Grb-2 binding to p185~(erbB2) to recruit its downstream target SOS to the membrane. Then, transcription itself is orchestrated by a plethora of transcription factors, activators, and suppressors, whose assembly is poorly understood but clearly important. Given the ubiquitous nature of these relationships, and the knowledge that inappropriate protein-protein binding can lead to disease, it should not be surprising that protein-protein interactions have attracted the attention of scientists in the pharmaceutical industry and elsewhere who are interested in producing inhibitors for use as biochemical tools or therapeutic agents. Indeed, there are ample examples in the literature of the use of antibodies, dominant negative proteins, or medium-sized peptides to inhibit particular protein-protein assemblies. In contrast, the discovery of small "drug-like" molecules that can perform a similar function has proven difficult.