HIV Protease Inhibitors

Abstract

In the history of drug development, no molecular target has attracted more attention in a shorter period of time than the protease from human immunodeficiency virus 1 (HIV-1). The human immunodeficiency virus was the first new pathogenic agent to be dissected at the structural and functional level by the tools of modern interdisciplinary science. Advances in recombinant DNA technology, rapid DNA sequence analysis, and detection and amplification of viral nucleic acid from tissue samples were initially used to characterize and analyze the virus, a retrovirus that uses reverse transcriptase to copy its RNA genome, and its constituent gene products. For a review of the molecular biology of retroviruses, see Ref. [1]. One of those gene products, reverse transcriptase, was the target for the first nucleoside-derived enzyme inhibitors that provided the initial hope of reducing the mortality due to AIDS. It became clear, however, from early clinical studies that combination therapy with more than one drug directed against reverse transcriptase provided superior clinical outcomes and that new antiretroviral agents with new mechanisms of action would also be needed to provide long-termsuppression of viremia and consequent reductions in mortality and comorbidities [2]. This drug discovery challenge was met by both academic and corporate research on a global scale.