Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity

FASEB J. 2011 Apr;25(4):1230-43. doi: 10.1096/fj.10-167627. Epub 2011 Jan 3.

Abstract

The chemokine receptor CCR5 is utilized as a critical coreceptor by most primary HIV-1 strains. While the lack of structural information on CCR5 has hampered the rational design of specific inhibitors, mimetics of the chemokines that naturally bind CCR5 can be molecularly engineered. We used a structure-guided approach to design peptide mimetics of the N-loop and β1-strand regions of regulated on activation normal T-cell-expressed and secreted (RANTES)/CCL5, which contain the primary molecular determinants of HIV-1 blockade. Rational modifications were sequentially introduced into the N-loop/β1-strand sequence, leading to the generation of mimetics with potent activity against a broad spectrum of CCR5-specific HIV-1 isolates (IC(50) range: 104-640 nM) but lacking activity against CXCR4-specific HIV-1 isolates. Functional enhancement was initially achieved with the stabilization of the N loop in the β-extended conformation adopted in full-length RANTES, as confirmed by nuclear magnetic resonance (NMR) analysis. However, the most dramatic increase in antiviral potency resulted from the engraftment of an in silico-optimized linker segment designed using de novo structure-prediction algorithms to stabilize the C-terminal α-helix and experimentally validated by NMR. Our mimetics exerted CCR5-antagonistic effects, demonstrating that the antiviral and proinflammatory functions of RANTES can be uncoupled. RANTES peptide mimetics provide new leads for the development of safe and effective HIV-1 entry inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Biomimetic Materials / chemical synthesis*
  • CCR5 Receptor Antagonists*
  • Chemokine CCL5 / chemical synthesis*
  • Chemotaxis / drug effects
  • HIV-1 / drug effects*
  • Hydrophobic and Hydrophilic Interactions
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemical synthesis*
  • Peptides / pharmacology
  • Protein Conformation
  • Protein Engineering
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases / drug effects

Substances

  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Chemokine CCL5
  • Peptides
  • p38 Mitogen-Activated Protein Kinases