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Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.

ABSTRACT: The HIV-1 envelope gp120/gp41 glycoprotein complex plays a critical role in virus-host cell membrane fusion and has been a focus for the development of HIV fusion inhibitors. In this Letter, we present the synthesis of dimers of HIV fusion inhibitor peptides C37H6 and CP32M, which target the trimeric gp41 in the pre-hairpin intermediate state to inhibit membrane fusion. Reactive peptide modules were synthesized using native chemical ligation and then assembled into dimers with varying linker lengths using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) 'click' chemistry. Cell-cell fusion inhibition assays demonstrated that dimers with a (PEG)7 linker showed enhanced antiviral potency over the corresponding monomers. Moreover, the bio-orthogonal nature of the CuAAC 'click' reaction provides a practical way to assemble heterodimers of HIV fusion inhibitors. Heterodimers consisting of the T20-sensitive strain inhibitor C37H6 and the T20-resistant strain inhibitor CP32M were produced that may have broader spectrum activities against both T20-sensitive and T20-resistant strains.

SUBMITTER: Xiao J

PROVIDER: S-EPMC3832134 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.

Xiao Junpeng J Tolbert Thomas J TJ

Bioorganic & medicinal chemistry letters 20130920 22

The HIV-1 envelope gp120/gp41 glycoprotein complex plays a critical role in virus-host cell membrane fusion and has been a focus for the development of HIV fusion inhibitors. In this Letter, we present the synthesis of dimers of HIV fusion inhibitor peptides C37H6 and CP32M, which target the trimeric gp41 in the pre-hairpin intermediate state to inhibit membrane fusion. Reactive peptide modules were synthesized using native chemical ligation and then assembled into dimers with varying linker len ...[more]

PMID: 24094817

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Project description:Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity.

Dataset Information

Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.

Publications

Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.

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