Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues

Abstract

The gag and pol genes of the human immunodeficiency virus type 1 (HIV-1) (ref. 1) are translated as two polyproteins, Pr55gag and Pr160gag-pol (refs 2-6), which are subsequently cleaved by the action of a virus-encoded protease into the four structural gag proteins of the virion core (p17, p24, p7 and p6) and the pol-encoded enzymes essential for retrovirus replication (protease, reverse transcriptase, ribonuclease H, and endonuclease). Mutational inactivation of the proteases of HIV-1 and other retroviruses results in immature, non-infectious virions, indicating that exogenous inhibition of the protease may represent an attractive approach to anti-AIDS therapy. Here we demonstrate that synthetic peptide analogues, which are potent inhibitors of purified HIV-1 protease, inhibit the processing of the viral polyproteins in cultures of HIV-1-infected T lymphocytes and attenuate viral infectivity.

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

“…For AZT and ddI, which, following their intracellular phosphorylation, act at the RT step (2), addition to the cells could be delayed until -5 hr (n = 5) after infection, and for the TIBO derivatives (R82150, R82913), which do not need intracellular transformations before they can interact with their target enzyme (HIV-1 RT) (4,6), the addition could be delayed by another 2 hr (n = 7). The protease inhibitor Ro31-8959 [compound XVII (14)], which interacts with a late event in the virus cycle (assembly of mature virions) (11)(12)(13)(14)(15)(16) was still effective if added as late as 21 hr after infection (n = 21). From the time-of-addition experiment, it appeared that the bicyclams JM1657 and JM2763 (n = 1 or 2) had to interact with a process following virus adsorption but preceding reverse transcription, which means virus-cell fusion and/or uncoating.…”

“…Other, nonnucleoside inhibitors ofthe HIV-1 RT have been recently identified (3)(4)(5) that directly interact with the enzyme at a specific target site, provisionally designated as the TIBO {tetrahydroimidazo [4,5,1- In addition to the RT, several other stages in the HIV replicative cycle, starting from the virion binding to the cells to the ultimate release (budding) of the virus particles from the cells, have been envisaged as targets for therapeutic intervention (7)(8)(9)(10). One such target is the HIV protease, and several HIV-1 protease inhibitors have been designed that appear to inhibit the enzyme, and consequently virus replication, with high specificity (11)(12)(13)(14)(15)(16). The viral protease is essential for proper assembly of mature, fully infectious HIV particles.…”

REVIEW : Recent advances in developing web-servers for predicting protein attributes

“…One is to target the HIV (human immunodeficiency virus) reverse transcriptase (see, e.g., [165][166][167][168][169][170][171]); the other is to design HIV protease inhibitors [128,136,138,139,[172][173][174].…”

Sequence‐Specific Resonance Assignments of the 1H‐NMR Spectra and Structural Characterization in Solution of the HIV‐1 Transframe Protein p6*

“…Prior to budding, Gag and Gag-Pol polyproteins assemble at the cytoplasmic membrane. Premature processing by a HIV protease activated too early prevents packing of the cleavage products into the virions, whereas inhibition of the protease results in immature and non-infectious particles (Facke et al, 1993;Gottlinger et al, 1989;Kaplan et al, 1993;Kohl et al, 1988;Krausslich, 1991;McQuade et al, 1990;Meek et al, 1990). There is evidence from in vitro transcription-translation assays that the frame shift protein p6* inhibits the processing activity of the HIV protease by blocking the active site in a manner similar to the pepsinogen N-terminal prosegment (James and Sielecki, 1986;Partin et al, 1991 ;Zybarth and Carter, 1995).…”