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

Paolo Lusso, Luca Vangelista, Raffaello Cimbro, Massimiliano Secchi, Francesca Sironi, Renato Longhi, Marina Faiella, Ornella Maglio, Vincenzo Pavone

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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 (RAN-TES)/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 (IC50 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.

Original languageEnglish
Pages (from-to)1230-1243
Number of pages14
JournalFASEB Journal
Issue number4
Publication statusPublished - Apr 2011


  • AIDS
  • Antivirals
  • CCR5
  • Chemokines
  • Rational design
  • Viral receptors

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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