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antiviral activity against both viruses, as shown in Figure 1 [5].Further improvement of the HR2 HPIV3 peptide against both viruses was achieved bymutating three residues: Ala463→Ile, Gln479→Lys, and Lys480→Ile. The resultingcholesterol-tagged peptide was extremely potent against NiV, with an IC 50 of 20 pM in thepseudotype infection assay.Nipah virus (NiV) is an important zoonotic paramyxovirus, for which neither anantiviral therapy nor a vaccine are available. It causes seasonal outbreaks of encephalitis inAsia, with fatality of up to 70% of cases. In addition to acute infection, it may cause lateonset disease years after initial infection, and persistent neurological sequelae [6].We took advantage of the existence of a validated small animal model of NiVencephalitis to test the efficacy of our HPIV3-derived inhibitor in vivo. As shown in Figure2, prophylactic treatment with a low subcutaneous dose of the cholesterol-tagged peptide,initiated 2 days before infection with a lethal dose of virus, could completely protect goldenhamsters. Because of plasma protein binding, cholesterol-tagging extends the circulatoryhalf-life [2] and accordingly, the HPIV3 peptide could be dosed only once daily.Experiments are ongoing to test its protective efficacy when given post infection. TheFig. 2. Cholesterol-tagged HPIV3 peptide protects from lethal infection in vivo. Goldenhamsters (5/group) were injected subcutaneously with peptide (2 mg/kg) (filled circles) orvehicle (empty circles) 2 days before infection, and then every day for 14 days postinfection. The hamsters were infected by intraperitoneal inoculation of NiV, using 100xLD 50 . At day 10, there were no survivors in the control group. The sequence of the peptideis VALDPIDISIVLNKI KSDLEESKEWIRRSNKILDSI.findings described here further validate the concept that targeting inhibitors to lipid raftswhere fusion occurs, via cholesterol-tagging, is a simple, yet effective way of increasingtheir potency and their pharmacological properties. Work is ongoing on other viral families.AcknowledgmentsWe are grateful to E. Bianchi, A. Langella, A. Santoprete, M. Finotto, E. Capitò, F. Rech, G. Ciliberto,A. Kutcher, and J. Ledecky. This work was supported by a March of Dimes grant, Public HealthService grants AI076335 and AI31971 from NIAID, and NIH/NIAID Northeast Center of Excellencefor Bio-defense and Emerging Infectious Disease Research grant U54AI057158, to A.M. and M.P.References1. Eckert, D.M., Kim, P.S. Annu. Rev. Biochem. 70, 777-810 (2001).2. Ingallinella, P., et al. Proc. Natl. Acad. Sci. U.S.A. 106, 5801-5806 (2009).3. Lambert, D.M., et al. Proc. Natl. Acad. Sci. U.S.A. 93, 2186-91 (1996).4. Porotto, M., et al. J. Virol. 81, 10567-10574 (2007).5. Porotto, M., et al. J. Virol. 84, 6770-6778 (2010).6. Eaton, B.T., et al. Nat. Rev. Microbiol. 4, 23-35 (2006).299