Abstract
CCR5, the major HIV-1 coreceptor, is a primary target for HIV-1 entry inhibition strategies. CCL5/RANTES, a natural CCR5 ligand, is one of the most potent HIV-1 entry inhibitors and, therefore, an ideal candidate to derive HIV-1 blockers. Peptides spanning the RANTES N-loop/β1-strand region act as specific CCR5 antagonists, with their hydrophobic N- and C termini playing a crucial role in virus blockade. Here, hydrophobic surfaces were enhanced by tryptophan substitution of aromatic residues, highlighting position 27 as a critical hot spot for HIV-1 blockade. In a further molecular evolution step, C-terminal engraftment of RANTES 40' loop produced a peptide with the highest solubility and anti-HIV-1 activity. These modified peptides represent leads for the development of effective HIV-1 inhibitors and microbicides.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / metabolism
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Anti-HIV Agents / pharmacology*
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Anti-HIV Agents / therapeutic use
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CCR5 Receptor Antagonists
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CD4-Positive T-Lymphocytes / virology
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Cells, Cultured
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Chemokine CCL5 / chemistry*
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Chemokine CCL5 / genetics
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Chemokine CCL5 / pharmacology*
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Chemokine CCL5 / therapeutic use
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HIV Infections / drug therapy
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HIV Infections / prevention & control
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HIV-1 / drug effects*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Macrophages / virology
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Models, Molecular
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Molecular Sequence Data
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Peptides / chemistry*
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Peptides / genetics
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Peptides / pharmacology*
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Peptides / therapeutic use
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Protein Conformation
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Virus Internalization / drug effects
Substances
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Anti-HIV Agents
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CCR5 Receptor Antagonists
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Chemokine CCL5
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Peptides
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Recombinant Proteins