Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain

Hongtao Zhang, Francesca Curreli, Xihui Zhang, Shibani Bhattacharya, Abdul A. Waheed, Alan Cooper, David Cowburn, Eric O. Freed, Asim K. Debnath

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Background: The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs.Results: Due to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC), sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease.Conclusions: These preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD.

Original languageEnglish (US)
Article number28
JournalRetrovirology
Volume8
DOIs
StatePublished - May 3 2011

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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    Zhang, H., Curreli, F., Zhang, X., Bhattacharya, S., Waheed, A. A., Cooper, A., Cowburn, D., Freed, E. O., & Debnath, A. K. (2011). Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain. Retrovirology, 8, [28]. https://doi.org/10.1186/1742-4690-8-28