title: Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.
abstract: Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapy-experienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC(90) values 15- to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC(50) only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC(90) values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility.
authors.affiliation: Merck Research Laboratories Peptide Center of Excellence and Department of Drug Metabolism, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ingallinella
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Neal A
authors.initials: NA
authors.lastname: Ladwa
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Wang
authors.forename: Renee
authors.initials: R
authors.lastname: Hrin
authors.forename: Maria
authors.initials: M
authors.lastname: Veneziano
authors.forename: Fabio
authors.initials: F
authors.lastname: Bonelli
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D023581:HIV Fusion Inhibitors; D002784:Cholesterol