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The Triple Threat of HIV-1 Protease Inhibitors

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The Future of HIV-1 Therapeutics

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 389))

Abstract

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.

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Abbreviations

HIV:

Human immunodeficiency virus

PR:

Protease

PI:

Protease inhibitor

RT:

Reverse transcriptase

IN:

Integrase

TF:

Transframe

MA:

Matrix

CA:

Capsid

NC:

Nucleocapsid

SP1:

Spacer peptide 1

SP2:

Spacer peptide 2

Env:

Envelope

CT:

Cytoplasmic tail

DRV:

Darunavir

TPV:

Tipranavir

SQV:

Saquinavir

NNRTI:

Non-nucleoside reverse transcriptase inhibitor

NRTI:

Nucleoside reverse transcriptase inhibitor

INSTI:

Integrase strand transfer inhibitor

AZT:

Zidovudine

RTC:

Reverse transcription complex

RNP:

Ribonucleoprotein

PIC:

Pre-integration complex

NPC:

Nuclear pore complex

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Acknowledgments

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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Authors and Affiliations

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

    Marc Potempa & Ronald Swanstrom

  2. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA

    Sook-Kyung Lee, Richard Wolfenden & Ronald Swanstrom

  3. UNC Center for AIDS Research, University of North Carolina, Chapel Hill, NC, 27599, USA

    Ronald Swanstrom

  4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA

    Ronald Swanstrom

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  1. Marc Potempa
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  2. Sook-Kyung Lee
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  3. Richard Wolfenden
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  4. Ronald Swanstrom
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Correspondence to Ronald Swanstrom .

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Editors and Affiliations

  1. Departments of Molecular and Experimental Medicine and Immunology and Microbial Science (MEM 131), The Scripps Research Institute, La Jolla, California, USA

    Bruce E. Torbett

  2. Department of Integrative Structural and Computational Biology, and RCSB Protein Data Bank, The Scripps Research Institute, La Jolla, California, USA

    David S. Goodsell

  3. Department of Pathology, University of California, San Diego, La Jolla, California, USA

    Douglas D. Richman

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Potempa, M., Lee, SK., Wolfenden, R., Swanstrom, R. (2015). The Triple Threat of HIV-1 Protease Inhibitors. In: Torbett, B., Goodsell, D., Richman, D. (eds) The Future of HIV-1 Therapeutics. Current Topics in Microbiology and Immunology, vol 389. Springer, Cham. https://doi.org/10.1007/82_2015_438

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