title: Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1 beta/CCL4.
abstract: The HIV coreceptor CCR5 is a validated target for both the prevention and therapy of HIV infection. PSC-RANTES, an N-terminally modified analogue of one of the natural chemokine ligands of CCR5 (RANTES/CCL5), is a potent inhibitor of HIV entry into target cells. Here, we set out to engineer the anti-HIV activity of PSC-RANTES into another natural CCR5 ligand (MIP-1beta/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1beta/CCL4 analogues that retain the receptor binding profile of MIP-1beta/CCL4, but acquire the very high anti-HIV potency and characteristic inhibitory mechanism of PSC-RANTES. Unexpectedly, we discovered that in addition to N-terminal structures from PSC-RANTES, the side chain of Lys33 is also necessary for full anti-HIV potency.
authors.affiliation: Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gaertner
authors.forename: Olivier
authors.initials: O
authors.lastname: Lebeau
authors.forename: Irène
authors.initials: I
authors.lastname: Borlat
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cerini
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dufour
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kuenzi
authors.forename: Astrid
authors.initials: A
authors.lastname: Melotti
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fish
authors.forename: Robin
authors.initials: R
authors.lastname: Offord
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Springael
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000235:genetics / Q000627:therapeutic use*; D018946:Chemokine CCL5 / Q000235:genetics / Q000627:therapeutic use*; D015195:Drug Design; D006678:HIV / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D054407:Chemokine CCL4; D018946:Chemokine CCL5; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-