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Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer


The zinc fingers of the HIV-1 nucleocapsid protein, NCp7, are prime targets for antiretroviral therapeutics. Here we show that S-acyl-2-mercaptobenzamide thioester (SAMT) chemotypes inhibit HIV by modifying the NCp7 region of Gag in infected cells, thereby blocking Gag processing and reducing infectivity. The thiol produced by SAMT reaction with NCp7 is acetylated by cellular enzymes to regenerate active SAMTs via a recycling mechanism unique among small-molecule inhibitors of HIV.

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Figure 1: SAMT-247 covalently modifies the Gag polyprotein, and the thiol released by reaction is acetylated intracellularly to form an active thioester.
Figure 2: A thioether prodrug confirms thiol acetylation and inhibits HIV.


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The authors thank T. Hartman (ImQuest Biosciences) for antiviral assays, E. Chertova (US National Cancer Institute at Frederick) for HPLC separation of Gag and P. Srivastava (US National Cancer Institute) for synthesis of 14C–SAMT-247. The authors thank J.A. Turpin and P.F. Kiser for helpful discussion. This research was supported by the US National Institutes of Health Intramural AIDS Targeted Antiretroviral Program (L.M.M.J., R.H., M.L.S., E.A.), the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (D.W., Q.X., D.H.A.) and with federal funds from the US National Cancer Institute under Contracts No. HHSN261200800001E and No. N01-CO-12400 (D.E.O., L.V.C.).

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L.M.M.J., D.E.O., R.H., M.L.S., J.K.I., D.H.A. and E.A. conceived experiments; L.M.M.J., D.E.O., R.H., L.V.C., D.W., Q.X. and J.K.I. performed experiments; L.M.M.J., D.E.O., M.L.S., J.K.I., D.H.A. and E.A. composed the manuscript.

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Correspondence to Ettore Appella.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Table 1 and Supplementary Figures 1–5 (PDF 1088 kb)

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Jenkins, L., Ott, D., Hayashi, R. et al. Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer. Nat Chem Biol 6, 887–889 (2010).

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