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Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.

TitleAddition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.
Publication TypeJournal Article
Year of Publication2009
AuthorsIngallinella P, Bianchi E, Ladwa NA, Wang Y-J, Hrin R, Veneziano M, Bonelli F, Ketas TJ, Moore JP, Miller MD, Pessi A
JournalProc Natl Acad Sci U S A
Date Published2009 Apr 7
KeywordsAnimals, Cholesterol, Dose-Response Relationship, Drug, Drug Delivery Systems, Half-Life, HeLa Cells, HIV Fusion Inhibitors, HIV Infections, Humans, Inhibitory Concentration 50, Mice, Structure-Activity Relationship

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19297617
PubMed Central IDPMC2667053
Grant ListU19 AI65413 / AI / NIAID NIH HHS / United States
U19 AI76982 / AI / NIAID NIH HHS / United States

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