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 journalArticle

16 Citations (Scopus)

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 (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 (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.

Original languageEnglish
Pages (from-to)1230-1243
Number of pages14
JournalFASEB Journal
Volume25
Issue number4
DOIs
Publication statusPublished - Apr 2011
Externally publishedYes

Fingerprint

Chemokine CCL5
HIV-1
Peptides
Antiviral Agents
Nuclear magnetic resonance
T-cells
Chemokine Receptors
Chemokines
Magnetic Resonance Spectroscopy
HIV Fusion Inhibitors
Conformations
Stabilization
Chemical activation
Computer Simulation
T-Lymphocytes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Lusso, P., Vangelista, L., Cimbro, R., Secchi, M., Sironi, F., Longhi, R., ... Pavone, V. (2011). Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. FASEB Journal, 25(4), 1230-1243. https://doi.org/10.1096/fj.10-167627

Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. / Lusso, Paolo; Vangelista, Luca; Cimbro, Raffaello; Secchi, Massimiliano; Sironi, Francesca; Longhi, Renato; Faiella, Marina; Maglio, Ornella; Pavone, Vincenzo.

In: FASEB Journal, Vol. 25, No. 4, 04.2011, p. 1230-1243.

Research output: Contribution to journalArticle

Lusso, P, Vangelista, L, Cimbro, R, Secchi, M, Sironi, F, Longhi, R, Faiella, M, Maglio, O & Pavone, V 2011, 'Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity', FASEB Journal, vol. 25, no. 4, pp. 1230-1243. https://doi.org/10.1096/fj.10-167627
Lusso, Paolo ; Vangelista, Luca ; Cimbro, Raffaello ; Secchi, Massimiliano ; Sironi, Francesca ; Longhi, Renato ; Faiella, Marina ; Maglio, Ornella ; Pavone, Vincenzo. / Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. In: FASEB Journal. 2011 ; Vol. 25, No. 4. pp. 1230-1243.
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