title: Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors.
abstract: We have used total chemical synthesis to perform high-resolution dissection of the pharmacophore of a potent anti-HIV protein, the aminooxypentane oxime of [glyoxylyl1]RANTES(2-68), known as AOP-RANTES, of which we designed and made 37 analogs. All involved incorporation of one or more rationally chosen nonnatural noncoded structures, for which we found a clear comparative advantage over coded ones. We investigated structure-activity relationships in the pharmacophore by screening the analogs for their ability to block the HIV entry process and produced a derivative, PSC-RANTES [N-nonanoyl, des-Ser1[L-thioproline2, L-cyclohexylglycine3]-RANTES(2-68)], which is 50 times more potent than AOP-RANTES. This promising group of compounds might be optimized yet further as potential prophylactic and therapeutic anti-HIV agents. The remarkable potency of our RANTES analogs probably involves the unusual mechanism of intracellular sequestration of CC-chemokine receptor 5 (CCR5), and it has been suggested that this arises from enhanced affinity for the receptor. We found that inhibitory potency and capacity to induce CCR5 down-modulation do appear to be correlated, but that unexpectedly, inhibitory potency and affinity for CCR5 do not. We believe this study represents the proof of principle for the use of a medicinal chemistry approach, above all one showing the advantage of noncoded structures, to the optimization of the pharmacological properties of a protein. Medicinal chemistry of small molecules is the foundation of modern pharmaceutical practice, and we believe we have shown that techniques have now reached the point at which the approach could also be applied to the many macromolecular drugs now in common use.
authors.affiliation: Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1211 Geneva 4, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
authors.forename: Hubert
authors.initials: H
authors.lastname: Gaertner
authors.forename: Jill
authors.initials: J
authors.lastname: Wilken
authors.forename: Darren
authors.initials: D
authors.lastname: Thompson
authors.forename: Richard
authors.initials: R
authors.lastname: Fish
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramos
authors.forename: Cristina
authors.initials: C
authors.lastname: Pastore
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dufour
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cerini
authors.forename: Astrid
authors.initials: A
authors.lastname: Melotti
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.forename: Laurent
authors.initials: L
authors.lastname: Picard
authors.forename: Marc
authors.initials: M
authors.lastname: Alizon
authors.forename: Donald
authors.initials: D
authors.lastname: Mosier
authors.forename: Stephen
authors.initials: S
authors.lastname: Kent
authors.forename: Robin
authors.initials: R
authors.lastname: Offord
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016466:CHO Cells; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D051379:Mice; D016513:Mice, SCID; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D012367:RNA, Viral; D019713:Receptors, CCR5