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The triple threat of HIV-1 protease inhibitors. | LitMetric

The triple threat of HIV-1 protease inhibitors.

Curr Top Microbiol Immunol

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, 27599, USA.

Published: July 2015

AI Article Synopsis

  • * Protease inhibitors (PIs) target the HIV-1 PR, affecting multiple stages of the viral life cycle, which causes their action to mimic that of entry and reverse transcription inhibitors.
  • * The chapter discusses three main effects of PIs: a cooperative dose-response for inhibition, their wide-ranging impact on various viral life cycle stages, and their potential as transition state analogs that may reduce the virus's ability to develop resistance against single drug therapies.

Article Abstract

Newly released human immunodeficiency virus type 1 (HIV-1) particles obligatorily undergo a maturation process to become infectious. The HIV-1 protease (PR) initiates this step, catalyzing the cleavage of the Gag and Gag-Pro-Pol structural polyproteins. Proper organization of the mature virus core requires that cleavage of these polyprotein substrates proceeds in a highly regulated, specific series of events. The vital role the HIV-1 PR plays in the viral life cycle has made it an extremely attractive target for inhibition and has accordingly fostered the development of a number of highly potent substrate-analog inhibitors. Though the PR inhibitors (PIs) inhibit only the HIV-1 PR, their effects manifest at multiple different stages in the life cycle due to the critical importance of the PR in preparing the virus for these subsequent events. Effectively, PIs masquerade as entry inhibitors, reverse transcription inhibitors, and potentially even inhibitors of post-reverse transcription steps. In this chapter, we review the triple threat of PIs: the intermolecular cooperativity in the form of a cooperative dose-response for inhibition in which the apparent potency increases with increasing inhibition; the pleiotropic effects of HIV-1 PR inhibition on entry, reverse transcription, and post-reverse transcription steps; and their potency as transition state analogs that have the potential for further improvement that could lead to an inability of the virus to evolve resistance in the context of single drug therapy.

Download full-text PDF

Source
http://dx.doi.org/10.1007/82_2015_438DOI Listing

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