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Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag?TSG101 interaction

Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag?TSG101 interaction
Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag?TSG101 interaction
The egress of HIV particles from virus-infected cells is accomplished by the recruitment of proteins that normally mediate host cell endocytic functions. This process requires interaction of the HIV Gag protein with the host protein TSG101 (tumor susceptibility gene 101). Here, we report the use of a bacterial reverse two-hybrid system to identify cyclic peptides that interfere with the Gag?TSG101 interaction and the finding that a five amino acid peptide discovered by this approach can disrupt the interaction and consequently inhibit HIV egress. The inhibiting molecule, which was selected from a cyclic peptide library containing 3.2 × 106 members, differs in primary sequence from the interacting sites of either TSG101 or Gag. Addition of cyclic peptide tagged with an HIV Tat sequence, which previously has been shown to enhance protein translocation across plasma membranes, to cultured human cells inhibited the production of virus-like particles (VLPs) by these cells (IC50 of 7 ?M), and this inhibition occurred in the absence of adverse affects on normal endocytic functions mediated by TSG101. A mutant Gag protein not dependent on TSG101 for release was unaffected by the cyclic peptide. Our findings, which suggest that interference with the TSG101?Gag interaction by cyclic peptides may be of practical use in the treatment of HIV infections, identify a specific cyclic peptide that reduces VLP release by this mechanism; they also demonstrate that the efficiency of interference with protein?protein interactions by cyclic peptides can be enhanced by tagging the peptides with translocation-promoting sequences. Collectively our results support the notion that small molecule therapeutics that inhibit specific interactions between viral and host proteins may have general applicability in antiviral therapy.
1554-8929
757-764
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Lu, Quan
e4979177-dd04-4c12-855a-88913fc5f49b
Gam, Jongsik
c2f06b43-c546-4462-b924-fa21da72a80d
Pans, Hui
920ca1fe-e8d2-48e7-bf60-bbd0974dd5a5
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Cohen, Stanley N.
62f8b9a8-9e3b-481c-8593-4cd53165ad74
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Lu, Quan
e4979177-dd04-4c12-855a-88913fc5f49b
Gam, Jongsik
c2f06b43-c546-4462-b924-fa21da72a80d
Pans, Hui
920ca1fe-e8d2-48e7-bf60-bbd0974dd5a5
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Cohen, Stanley N.
62f8b9a8-9e3b-481c-8593-4cd53165ad74

Tavassoli, Ali, Lu, Quan, Gam, Jongsik, Pans, Hui, Benkovic, Stephen J. and Cohen, Stanley N. (2008) Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag?TSG101 interaction. ACS Chemical Biology, 3 (12), 757-764. (doi:10.1021/cb800193n). (PMID:19053244)

Record type: Article

Abstract

The egress of HIV particles from virus-infected cells is accomplished by the recruitment of proteins that normally mediate host cell endocytic functions. This process requires interaction of the HIV Gag protein with the host protein TSG101 (tumor susceptibility gene 101). Here, we report the use of a bacterial reverse two-hybrid system to identify cyclic peptides that interfere with the Gag?TSG101 interaction and the finding that a five amino acid peptide discovered by this approach can disrupt the interaction and consequently inhibit HIV egress. The inhibiting molecule, which was selected from a cyclic peptide library containing 3.2 × 106 members, differs in primary sequence from the interacting sites of either TSG101 or Gag. Addition of cyclic peptide tagged with an HIV Tat sequence, which previously has been shown to enhance protein translocation across plasma membranes, to cultured human cells inhibited the production of virus-like particles (VLPs) by these cells (IC50 of 7 ?M), and this inhibition occurred in the absence of adverse affects on normal endocytic functions mediated by TSG101. A mutant Gag protein not dependent on TSG101 for release was unaffected by the cyclic peptide. Our findings, which suggest that interference with the TSG101?Gag interaction by cyclic peptides may be of practical use in the treatment of HIV infections, identify a specific cyclic peptide that reduces VLP release by this mechanism; they also demonstrate that the efficiency of interference with protein?protein interactions by cyclic peptides can be enhanced by tagging the peptides with translocation-promoting sequences. Collectively our results support the notion that small molecule therapeutics that inhibit specific interactions between viral and host proteins may have general applicability in antiviral therapy.

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e-pub ahead of print date: 24 November 2008
Published date: 19 December 2008
Organisations: Chemistry

Identifiers

Local EPrints ID: 158653
URI: http://eprints.soton.ac.uk/id/eprint/158653
ISSN: 1554-8929
PURE UUID: 4e22c76a-c783-41e3-a9f6-da80376512d6
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 22 Jun 2010 13:53
Last modified: 17 Dec 2019 01:45

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