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. 2006 Nov;72(2):89-99.
doi: 10.1016/j.antiviral.2006.03.015. Epub 2006 Apr 21.

Inhibition of HIV-1 replication by a peptide dimerization inhibitor of HIV-1 protease

David A Davis  1 , Cara A Brown, Kathleen E Singer, Victoria Wang, Joshua Kaufman, Stephen J Stahl, Paul Wingfield, Kenji Maeda, Shigeyoshi Harada, Kazuhisa Yoshimura, Pope Kosalaraksa, Hiroaki Mitsuya, Robert Yarchoan
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Inhibition of HIV-1 replication by a peptide dimerization inhibitor of HIV-1 protease

David A Davis et al. Antiviral Res. 2006 Nov.

Abstract

Peptides based on the amino (N) and carboxy (C)-terminal regions of human immunodeficiency virus type-1 (HIV-1) protease and on the C-terminus of p6* can inhibit HIV-1 protease activity by preventing dimerization. We developed a peptide dimerization inhibitor, P27, that included these domains and a cell permeable domain derived from HIV-1 Tat. P27 inhibited wild type (WT) and protease inhibitor (PI)-resistant HIV-1 protease (IC50: 0.23-0.32 microM). Kinetic and biochemical assays confirmed that P27 inhibits protease dimerization. Fluorescein-labeled peptide accumulated in MT-2 cells and protected acutely infected MT-2 cells from HIV-1-induced cytotoxicity (IC50: 5.1 microM). P27 also inhibited p24 accumulation from H9 and U937 cells chronically infected with WT or PI-resistant HIV-1. Immunoblot analysis on the supernatants and infected cells revealed a block in virus release by P27 rather than an inhibition of polyprotein processing. However, inhibition of p55 Gag processing by active-site inhibitors was enhanced when combined with P27, suggesting that P27 can affect protease function in maturing virions. Although P27 was rationally designed to block dimerization of the mature HIV-1 protease, the effects of P27 on HIV-1 replication may be related to partial inhibition of Gag-Pol processing leading to a disruption in virus release.

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