The Triple Threat of HIV-1 Protease Inhibitors

  • Marc Potempa
  • Sook-Kyung Lee
  • Richard Wolfenden
  • Ronald SwanstromEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 389)


HIV Maturation. This illustration shows an immature virion in the process of maturation at bottom right and a nearly mature virion at upper left. HIV protease (A) is cleaving the Gag and Gag-Pol proteins into functional proteins

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.


Nuclear Pore Complex Cleavage Event Transition State Analog Reverse Transcription Complex Gp41 Fusion Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Human immunodeficiency virus




Protease inhibitor


Reverse transcriptase












Spacer peptide 1


Spacer peptide 2




Cytoplasmic tail








Non-nucleoside reverse transcriptase inhibitor


Nucleoside reverse transcriptase inhibitor


Integrase strand transfer inhibitor




Reverse transcription complex




Pre-integration complex


Nuclear pore complex



We thank Dr. Nicolas Sluis-Cremer for providing NNRTI and NRTI Ki values. Our own work is supported by the National Institutes of Health (NIH). M.P. is supported, in part, by NIH Training Grant T32 AI 07001-36. We also thank Dr. Celia Schiffer for many helpful discussions.


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Marc Potempa
    • 1
  • Sook-Kyung Lee
    • 2
  • Richard Wolfenden
    • 2
  • Ronald Swanstrom
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Microbiology and ImmunologyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of Biochemistry and BiophysicsUniversity of North CarolinaChapel HillUSA
  3. 3.UNC Center for AIDS ResearchUniversity of North CarolinaChapel HillUSA
  4. 4.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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