Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity(568 views) Lusso P, Vangelista L, Cimbro R, Secchi M, Sironi F, Longhi R, Faiella M, Maglio O, Pavone V
Keywords: Aids, Antivirals, Ccr5, Chemokines, Rational Design, Viral Receptors, Chemokine Receptor Ccr5, Chemokine Receptor Cxcr4, Guanine Nucleotide Binding Protein, Rantes, Algorithm, Alpha Helix, Antiviral Activity, Article, Beta 1 Protein Strand, Carboxy Terminal Sequence, Computer Model, Human Immunodeficiency Virus 1, Hydrophobicity, N Loop, Nuclear Magnetic Resonance, Priority Journal, Protein Structure, Amino Acid Sequence, Anti-Hiv Agents, Biomimetic Materials, Chemokine Ccl5, Chemotaxis, Hydrophobic And Hydrophilic Interactions, Biomolecular, P38 Mitogen-Activated Protein Kinases, Peptides, Protein Conformation, Protein Engineering, Signal Transduction, Structure-Activity Relationship,
Affiliations: *** IBB - CNR ***
Unit of Human Virology, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
National Research Council (CNR), Istituto di Chimica del Riconoscimento Molecolare (ICRM), Milan, Italy
Department of Chemistry, University of Naples Federico II, Naples, Italy
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, United States
Istituto di Biostrutture e Bioimmagini (IBB), National Research Council (CNR), 80134 Napoli, Italy
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Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity
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 beta 1-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/beta 1-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 beta-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 alpha-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.-Lusso, P., Vangelista, L., Cimbro, R., Secchi, M., Sironi, F., Longhi, R., Faiella, M., Maglio, O., Pavone, V. Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. FASEB J. 25, 1230-1243 (2011). www.fasebj.org
Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity