Protein-protein interaction targets to inhibit HIV-1 infection

Abstract

Efforts to interfere with four key protein-protein interactions in the HIV-1 lifecycle with the goal of achieving clinically-relevant, orally administered HIV-1 therapies are reviewed. These four targets: the HIV-1 gp120/human CD4 interaction, the HIV-1 gp41 six-helix bundle formation, the human LEDGF/p75-integrase interaction, and HIV-1 protease dimerization each present unique challenges to the discovery of viable small molecule inhibitors. Background information from the literature is provided. A class of inhibitors which target gp120 from which an orally dosed member has been advanced into Phase II clinical studies as well as other small molecule approaches to disrupt the gp120/CD4 interaction are discussed. The unrealized efforts to find a small-molecule inhibitor of gp41 six-helix bundle formation that is suitable for clinical studies are described, including a summary of the work on effective, peptidic inhibitors that lack the properties needed for oral use. An overview of the progress to identify small molecule inhibitors of the LEDGF/HIV-1 p75-integrase interaction and the dimerization of the HIV-1 protease enzyme describes the preclinical compounds of greatest interest and discusses the rationale behind their design/activity. © 2012 Springer-Verlag Berlin Heidelberg.