A New Generation of Peptide-based Inhibitors Targeting HIV-1 Reverse Transcriptase Conformational Flexibility.

International audienceThe biologically active form of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) is a heterodimer. The formation of RT is a two-step mechanism, including a rapid protein-protein interaction "the dimerization step," followed by conformational changes "the maturation step," yielding the biologically active form of the enzyme. We have previously proposed that the heterodimeric organization of RT constitutes an interesting target for the design of new inhibitors. Here, we propose a new class of RT inhibitors that targets protein-protein interactions and conformational changes involved in the maturation of heterodimeric reverse transcriptase. Based on a screen of peptides derived from the thumb domain of this enzyme, we have identified a short peptide P(AW) that inhibits the maturation step and blocks viral replication at subnanomolar concentrations. P(AW) only binds dimeric RT and stabilizes it in an inactive/non-processive conformation. From a mechanistic point of view, P(AW) prevents proper binding of primer/template by affecting the structural dynamics of the thumb/fingers of p66 subunit. Taken together, these results demonstrate that HIV-1 RT maturation constitutes an attractive target for AIDS chemotherapeutics

Early evolution of plasma soluble TNF-alpha p75 receptor as a marker of progression in treated HIV-infected patients.

International audienceAbstract We evaluated the prognostic value of different mediators of inflammation: TNF-alpha and its soluble receptor p75, platelet-activating factor, and glutathione tripeptide in a case-control study nested within a cohort of 1281 patients infected by the human immunodeficiency virus (HIV) started on highly active antiretroviral treatment (HAART). During the first year of HAART, 16 cases experienced an AIDS-defining event and 6 experienced an evolution of T CD4(+) cell count <100/mm(3). Forty-four controls who did not progress during the same follow-up period were matched for age, baseline CD4(+), and HIV-RNA. In the control group, plasma levels of TNF-alpha and its soluble receptor p75 decreased significantly from baseline to month 4: from 11.0 to 8.7 pg/ml (p < 0.001) and from 27.3 to 22.8 pg/ml (p < 0.003), respectively. Furthermore the decrease of TNF-alpha soluble receptor p75 was larger in nonprogressors than in progressors (p = 0.003). Measurement of TNF-alpha soluble receptor p75 may be of interest as an additional marker of early antiretroviral effect

Part 13: Synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 or pure antiretroviral activity

HIV-1 infection of the brain and PAF neurotoxicity are implicated in AIDS dementia complex. We previously reported that a trisubstituted piperazine derivative is able to diminish both HIV-1 replication in monocyte-derived macrophages and PAF-induced platelet aggregation. We report in this work new compounds obtained by modifying its piperazine substituents. The structure-activity relationship study shows that a better dual activity or even pure antiretroviral compounds can be obtained in this series. (c) 2006 Elsevier Ltd. All rights reserved

Structure-activity relationships in platelet-activating factor. Part 14: Synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity

As HIV-associated dementia prevalence has risen with the lifespan of HIV-infected individuals, there is an important need for antiretroviral and anti-inflammatory drugs targeting the central nervous system. Platelet-activating factor, a mediator of inflammation, is an HIV-induced neurotoxin secreted in the infected brain. In this work, we developed piperazine derivatives bearing a heterocyclic moiety as PAF-antagonists and HIV-1 replication inhibitors with micromolar potency. (c) 2006 Elsevier Ltd. All rights reserved