title: Enhancement of anti-HIV-1 activity by hot spot evolution of RANTES-derived peptides.
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.
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Secchi
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Lia
authors.initials: L
authors.lastname: Vassena
authors.forename: Francesca
authors.initials: F
authors.lastname: Sironi
authors.forename: Stephan
authors.initials: S
authors.lastname: Grzesiek
authors.forename: Paolo
authors.initials: P
authors.lastname: Lusso
authors.forename: Luca
authors.initials: L
authors.lastname: Vangelista
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008264:Macrophages / Q000821:virology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D010455:Peptides; D011994:Recombinant Proteins