Hepatitis C virus NS5A anchor peptide disrupts human immunodeficiency virus

Bobardt, Michael; Cheng, Guofeng; Witte, Lot de; Selvarajah, Suganya; Chatterji, Udayan; Sanders-Beer, Brigitte E.; Geijtenbeek, Teunis B. H.; Chisari, Francis V.; Gallay, Philippe

doi:10.1073/pnas.0801388105

Cited by 76 publications

(111 citation statements)

References 22 publications

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“…Also, amphipathic peptides derived from the NS5A protein of hepatitis C virus (HCV) can disrupt viral membranes physically and have been reported to inhibit a variety of enveloped viruses (16,17). These examples support the hypothesis that inhibitors that target and disrupt the lipid interfaces mediating virus-cell fusion could be developed as broad-spectrum antivirals.…”

mentioning

confidence: 53%

“…Physical disruption of viral particles has been proposed as the basis for the broadspectrum antiviral activity of a peptide derived from the NS5A protein of HCV (16,17). To determine if this disruption also was the mechanistic basis for LJ001's action, we treated RVFV MP-12 with LJ001 or DMSO and repurified the virus via banding through a density gradient.…”

Section: Virusmentioning

confidence: 99%

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A broad-spectrum antiviral targeting entry of enveloped viruses

Wolf

Freiberg²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

225

217

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We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.virology | viral entry | fusion inhibitor | small molecule | lipid membrane

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mentioning

confidence: 53%

Section: Virusmentioning

confidence: 99%

A broad-spectrum antiviral targeting entry of enveloped viruses

Wolf

Freiberg²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

225

217

View full text Add to dashboard Cite

show abstract

“…4). Prior to selection for in vivo efficacy evaluation here, each inhibitor was shown to efficiently inhibit HIV in vitro (3,5,39,43,50,52,54,56). Our experimental approach for testing these six inhibitors was a single dose of the product administered prior to exposure rather than the two doses of drug administered within 24 h as used in CAPRISA 004 (1).…”

Section: Resultsmentioning

confidence: 99%

“…C52L is a sequence-modified C-peptide version of T-20 that binds to the N-terminal heptad repeat of gp41 to block fusion between the virion and the cell membranes (10,50). C5A is an amphipathic ␣-helical peptide HIV inhibitor derived from the hepatitis C virus NS5A anchor domain (5). C5A acts at preentry by disrupting the integrity of the viral membrane and the mature viral core.…”

Section: Vol 85 2011 One Percent Tenofovir Limits Vaginal Hiv Transmentioning

confidence: 99%

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Denton

Othieno

Martinez-Torres

et al. 2011

J Virol

130

150

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“…Importantly, these predictions were tested and validated by molecular virology experiments which demonstrated AH peptide has broad-spectrum antiviral activity against HCV, HIV, herpes simplex virus, and dengue virus, as well as many more deadly pathogens [44][45][46]. As such, the AH peptide represents the first in class of lipid envelope-rupturing antiviral agents.…”

Section: Introductionmentioning

confidence: 99%

Model Membrane Platforms for Biomedicine: Case Study on Antiviral Drug Development

Jackman

Cho

2012

Biointerphases

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As one of the most important interfaces in cellular systems, biological membranes have essential functions in many activities such as cellular protection and signaling. Beyond their direct functions, they also serve as scaffolds to support the association of proteins involved in structural support, adhesion, and transport. Unfortunately, biological processes sometimes malfunction and require therapeutic intervention. For those processes which occur within or upon membranes, it is oftentimes difficult to study the mechanism in a biologically relevant, membranous environment. Therefore, the identification of direct therapeutic targets is challenging. In order to overcome this barrier, engineering strategies offer a new approach to interrogate biological activities at membrane interfaces by analyzing them through the principles of the interfacial sciences. Since membranes are complex biological interfaces, the development of simplified model systems which mimic important properties of membranes can enable fundamental characterization of interaction parameters for such processes. We have selected the hepatitis C virus (HCV) as a model viral pathogen to demonstrate how model membrane platforms can aid antiviral drug discovery and development. Responsible for generating the genomic diversity that makes treating HCV infection so difficult, viral replication represents an ideal step in the virus life cycle for therapeutic intervention. To target HCV genome replication, the interaction of viral proteins with model membrane platforms has served as a useful strategy for target identification and characterization. In this review article, we demonstrate how engineering approaches have led to the discovery of a new functional activity encoded within the HCV nonstructural 5A protein. Specifically, its N-terminal amphipathic, α-helix (AH) can rupture lipid vesicles in a size-dependent manner. While this activity has a number of exciting biotechnology and biomedical applications, arguably the most promising one is in antiviral medicine. Based on the similarities between lipid vesicles and the lipid envelopes of virus particles, experimental findings from model membrane platforms led to the prediction that a range of medically important viruses might be susceptible to rupturing treatment with synthetic AH peptide. This hypothesis was tested and validated by molecular virology studies. Broad-spectrum antiviral activity of the AH peptide has been identified against HCV, HIV, herpes simplex virus, and dengue virus, and many more deadly pathogens. As a result, the AH peptide is the first in class of broad-spectrum, lipid envelope-rupturing antiviral agents, and has entered the drug pipeline. In summary, engineering strategies break down complex biological systems into simplified biomimetic models that recapitulate the most important parameters. This approach is particularly advantageous for membrane-associated biological processes because model membrane platforms provide more direct characterization of target interactions than is possible with other methods. Consequently, model membrane platforms hold great promise for solving important biomedical problems and speeding up the translation of biological knowledge into clinical applications.

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Hepatitis C virus NS5A anchor peptide disrupts human immunodeficiency virus

Cited by 76 publications

References 22 publications

A broad-spectrum antiviral targeting entry of enveloped viruses

A broad-spectrum antiviral targeting entry of enveloped viruses

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Model Membrane Platforms for Biomedicine: Case Study on Antiviral Drug Development

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