Design of antiviral stapled peptides containing a biphenyl cross-linker

Avinash Muppidi; Hongtao Zhang; Francesca Curreli; Nan Li; Asim K Debnath; Qing Lin

doi:10.1016/j.bmcl.2014.02.038

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. Epub 2014 Feb 22.

Authors

Avinash Muppidi¹, Hongtao Zhang², Francesca Curreli², Nan Li¹, Asim K Debnath³, Qing Lin⁴

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Biphenyl Compounds / chemistry*
Cell Line
Cross-Linking Reagents / chemical synthesis
Cross-Linking Reagents / chemistry
Cross-Linking Reagents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
HIV-1 / drug effects*
Humans
Microbial Sensitivity Tests
Peptides / chemical synthesis
Peptides / chemistry
Peptides / pharmacology*
Structure-Activity Relationship

Substances

Anti-HIV Agents
Biphenyl Compounds
Cross-Linking Reagents
Peptides
diphenyl

Abstract

Publication types

MeSH terms

Substances

Grants and funding