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A peptide inhibitor of HIV-1 assembly in vitro

Nature Structural & Molecular Biology volume 12, pages 671–677 (2005)Cite this article

Abstract

Formation of infectious HIV-1 involves assembly of Gag polyproteins into immature particles and subsequent assembly of mature capsids after proteolytic disassembly of the Gag shell. We report a 12-mer peptide, capsid assembly inhibitor (CAI), that binds the capsid (CA) domain of Gag and inhibits assembly of immature- and mature-like capsid particles in vitro. CAI was identified by phage display screening among a group of peptides with similar sequences that bind to a single reactive site in CA. Its binding site was mapped to CA residues 169–191, with an additional contribution from the last helix of CA. This result was confirmed by a separate X-ray structure analysis showing that CAI inserts into a conserved hydrophobic groove and alters the CA dimer interface. The CAI binding site is a new target for antiviral development, and CAI is the first known inhibitor directed against assembly of immature HIV-1.

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Figure 1: Illustration of Gag-derived proteins.
Figure 2: Results of ELISAs showing peptide competition for phage-CAI binding to CA.
Figure 3: Inhibition of assembly of immature-like particles in vitro.
Figure 4: Inhibition of assembly of mature-like particles in vitro.
Figure 5
Figure 6: NMR chemical shift perturbation analysis.

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Acknowledgements

This work was supported in part by the Deutsche Forschungsgemeinschaft and the DAAD-PROCOPE program. J.W. and S.F. thank the Wellcome Trust for support of the NMR facility. We thank F. Rey for helpful discussions.

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Authors and Affiliations

  1. Department of Virology, Universitätsklinikum Heidelberg, Heidelberg, 69120, Germany

    Jana Sticht, Jochen Bodem, Barbara Müller & Hans-Georg Kräusslich

  2. Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt/Main, 60596, Germany

    Michael Humbert & Ursula Dietrich

  3. School of Biological Sciences, University of Southampton, Southampton, SO16 7PX, UK

    Stuart Findlow & Jörn Werner

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  1. Jana Sticht
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Correspondence to Hans-Georg Kräusslich.

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Sticht, J., Humbert, M., Findlow, S. et al. A peptide inhibitor of HIV-1 assembly in vitro. Nat Struct Mol Biol 12, 671–677 (2005). https://doi.org/10.1038/nsmb964

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