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

@article{citeulike:4306696, abstract = {10.1073/pnas.0901007106 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\^{a}€“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 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 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 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.}, author = {Ingallinella, Paolo and Bianchi, Elisabetta and Ladwa, Neal A. and Wang, Ying-Jie and Hrin, Renee and Veneziano, Maria and Bonelli, Fabio and Ketas, Thomas J. and Moore, John P. and Miller, Michael D. and Pessi, Antonello}, citeulike-article-id = {4306696}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0901007106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/14/5801.full.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/14/5801.full.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19297617}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19297617}, day = {7}, doi = {10.1073/pnas.0901007106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {fusion, hiv, raft}, month = {April}, number = {14}, pages = {5801--5806}, posted-at = {2009-04-14 11:46:10}, priority = {2}, title = {Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency}, url = {http://dx.doi.org/10.1073/pnas.0901007106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:4306696 L3 - citeulike-article-id:4306696 N2 - 10.1073/pnas.0901007106 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 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 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 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. IS - 14 JF - Proceedings of the National Academy of Sciences EP - 5806 TI - Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency VL - 106 SP - 5801 KW - fusion KW - hiv KW - raft AU - Ingallinella, Paolo AU - Bianchi, Elisabetta AU - Ladwa, Neal AU - Wang, Ying-Jie AU - Hrin, Renee AU - Veneziano, Maria AU - Bonelli, Fabio AU - Ketas, Thomas AU - Moore, John AU - Miller, Michael AU - Pessi, Antonello PY - 2009/04/07/ UR - http://dx.doi.org/10.1073/pnas.0901007106 ER -