Design of antiviral stapled peptides containing a biphenyl cross-linker

  • Bioorg Med Chem Lett. 2014 Apr 1;24(7):1748-51. doi: 10.1016/j.bmcl.2014.02.038.
Avinash Muppidi  1 ,  Hongtao Zhang  2 ,  Francesca Curreli  2 ,  Nan Li  1 ,  Asim K Debnath  3 ,  Qing Lin  4
Affiliations
  • 1. Department of Chemistry, State University of New York at Buffalo, Buffalo, NY 14260, USA.
  • 2. Laboratory of Molecular Modeling and Drug Design, Lindsley F. Kimball Research Institute of the New York Blood Center, 310 E 67th Street, New York, NY 10065, USA.
  • 3. Laboratory of Molecular Modeling and Drug Design, Lindsley F. Kimball Research Institute of the New York Blood Center, 310 E 67th Street, New York, NY 10065, USA. Electronic address: [email protected].
  • 4. Department of Chemistry, State University of New York at Buffalo, Buffalo, NY 14260, USA. Electronic address: [email protected].
PMID: 24613163 DOI: 10.1016/j.bmcl.2014.02.038
Abstract

Here we report the design and synthesis of a panel of stapled peptides containing a distance-matching biphenyl cross-linker based upon a peptide capsid assembly inhibitor reported previously. Compared with the linear peptide, the biphenyl-stapled peptides exhibited significantly enhanced cell penetration and potent Antiviral activity in the cell-based Infection assays. Isothermal titration calorimetry and surface plasmon resonance experiments revealed that the most active stapled CAI peptide binds to the C-terminal domain of HIV capsid protein as well as envelop glycoprotein gp120 with low micromolar binding affinities, and as a result, inhibits both the HIV-1 virus entry and the virus assembly.

Keywords
HIV capsid; Peptides; Protein–protein interaction; Virus assembly; Virus entry.