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Originally published In Press as doi:10.1074/jbc.M008763200 on February 21, 2001

J. Biol. Chem., Vol. 276, Issue 20, 16674-16682, May 18, 2001
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Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays*

Robert KuheljDagger §, Christopher J. RizzoDagger , Chong-Hwan Chang, Prabhakar K. JadhavDagger Dagger , Eric M. Towler||**, and Bruce D. KorantDagger §§

From the Departments of Dagger  Virology and  Chemical and Physical Sciences, Experimental Station, DuPont Pharmaceuticals, Wilmington, Delaware 19880 and the || Protein Chemistry Laboratory, SAIC Frederick, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702

A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites. To identify compounds that could inhibit protein processing dependent on the HERV-K10 protease, a series of cyclic ureas that had previously been shown to inhibit HIV-1 protease was tested. Several symmetric bisamides acted as very potent inhibitors of both the truncated and full-length form of HERV-K10 protease, in subnanomolar or nanomolar range, respectively. One of the cyclic ureas, SD146, can inhibit the processing of in vitro translated HERV-K10 Gag polyprotein substrate by HERV-K10 protease. In addition, in virus-like particles isolated from the teratocarcinoma cell line NCCIT, there is significant accumulation of Gag and Gag-Pol precursors upon treatment with SD146, suggesting the compound efficiently blocks HERV-K Gag processing in cells. This is the first report of an inhibitor able to block cell-associated processing of Gag polypeptides of an endogenous retrovirus.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by the DuPont Pharmaceuticals Company Postdoctoral Program. Permanent address: Dept. of Biochemistry and Molecular Biology, Jozef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.

** Present address: Bayer Corp., Dept. of Protein Biosciences, 400 Morgan Lane, West Haven, Connecticut 06516.

Dagger Dagger Present address: Lilly Research Labs. Indianapolis, IN 46285.

§§ To whom correspondence should be addressed: DuPont Pharmaceuticals, Dept. of Virology, Experimental Station E336/22, P.O. Box 80336, Wilmington, DE 19880-0336. Tel.: 302-695-9493; Fax: 302-695-9420; E-mail: bruce.d.korant@dupontpharma.com.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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