A systematic evaluation of the inhibition of HIV-1 protease by its C- and N-terminal peptides

Franciskovich, Jeff; Houseman, Kathryn; Mueller, Richard A.; Chmielewski, Jean

doi:10.1016/s0960-894x(01)81271-3

Cited by 29 publications

(20 citation statements)

References 14 publications

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“…Several other structures derived from the terminal segments showed comparable inhibition [152,153]. Systematic study of the length requirements for the Nand C-terminal peptide needed for optimum HIV-1 protease inhibition were conducted [154]. The best inhibitory activity was obtained with sequences corresponding exactly to the full length β-strands in the four-stranded β-sheet region of the protease, lending support to the hypothesis that these peptides may interfere with the dimerization interface.…”

Section: C-terminus and N-terminus Peptides And Peptidomimetic Inhibimentioning

confidence: 74%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as potential targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

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Section: C-terminus and N-terminus Peptides And Peptidomimetic Inhibimentioning

confidence: 74%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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“…Short synthetic peptides corresponding to the amino‐acid sequences of the N‐ and C‐termini of HIV‐1 PR have been shown to inhibit proteolytic activity by binding to the inactive PR subunits and preventing their association into active dimer [16–19]. Peptides corresponding to the C‐terminal segment of the HIV‐1 matrix protein have also been found to elicit the same effect [20].…”

Section: Peptide‐based Inhibitors Of Pr Dimerizationmentioning

confidence: 99%

Modulation of the oligomeric structures of HIV‐1 retroviral enzymes by synthetic peptides and small molecules

Sluis‐Cremer

Tachedjian

2002

European Journal of Biochemistry

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The efficacy of antiretroviral agents approved for the treatment of HIV‐1 infection is limited by the virus's ability to develop resistance. As such there is an urgent need for new ways of thinking about anti‐HIV drug development, and accordingly novel viral and cellular targets critical to HIV‐1 replication need to be explored and exploited. The retroviral RNA genome encodes for three enzymes essential for viral replication: HIV‐1 protease (PR), HIV‐1 reverse transcriptase (RT) and HIV‐1 integrase (IN). The enzymatic functioning of each of these enzymes is entirely dependent on their oligomeric structures, suggesting that inhibition of subunit‐subunit assembly or modulation of their quaternary structures provide alternative targets for HIV‐1 inhibition. This review discusses the recent advances in the design and/or identification of synthetic peptides and small molecules that specifically target the subunit–subunit interfaces of these retroviral enzymes, resulting in the inactivation of their enzymatic functioning.

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“…[7] The protease termini b sheet interface has been explored as a dimerization inhibition target, and known inhibitors that target this region are able to block or disrupt the formation of the homodimer. [8] C-and N-terminal mimetic peptides [9][10][11] and lipopeptides [12][13][14] have proven to be efficient PR dimerization inhibitors. A bicyclic guanidinium group has been introduced between the peptidic and lipophilic moieties, [15] and the interface peptides have also been cross-linked with flexible, [16] semi-rigid, [17] or rigid spacers.…”

Section: Introductionmentioning

confidence: 99%

Toward the First Nonpeptidic Molecular Tong Inhibitor of Wild‐Type and Mutated HIV‐1 Protease Dimerization

et al. 2010

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Herein we describe the synthesis and HIV-1 protease (PR) inhibitory activity of 16 new peptidomimetic molecular tongs with a naphthalene scaffold. Their peptidic character was progressively decreased. Two of these molecules exhibited the best dimerization inhibition activity toward HIV-1 wild-type and multimutated ANAM-11 proteases obtained to date for this class of molecules (∼40 nM for wild-type PR and 100 nM for ANAM-11 PR). Although the peptidic character of one molecular tong was completely suppressed, the mechanism of inhibition and inhibitory potency toward both proteases were maintained.

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A systematic evaluation of the inhibition of HIV-1 protease by its C- and N-terminal peptides

Cited by 29 publications

References 14 publications

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Modulation of the oligomeric structures of HIV‐1 retroviral enzymes by synthetic peptides and small molecules

Toward the First Nonpeptidic Molecular Tong Inhibitor of Wild‐Type and Mutated HIV‐1 Protease Dimerization

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