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Originally published In Press as doi:10.1074/jbc.M403394200 on September 14, 2004

J. Biol. Chem., Vol. 279, Issue 47, 49055-49063, November 19, 2004
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Polyarginine Inhibits gp160 Processing by Furin and Suppresses Productive Human Immunodeficiency Virus Type 1 Infection*

Karen V. Kibler{ddagger}§, Akiko Miyazato{ddagger}§, Venkat S. R. K. Yedavalli{ddagger}, Andrew I. Dayton¶, Bertram L. Jacobs||, George Dapolito{ddagger}, Seong-jin Kim**, and Kuan-Teh Jeang{ddagger}{ddagger}{ddagger}

From the {ddagger}Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, the Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892-0460, the ||Biodesign Institute, Center for Infectious Disease and Vaccinology, Arizona State University, Tempe, Arizona 85287, and the **Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892-0460

Correct endoproteolytic maturation of gp160 is essential for the infectivity of human immunodeficiency virus type 1. This processing of human immunodeficiency virus-1 envelope protein, gp160, into gp120 and gp41 has been attributed to the activity of the cellular subtilisin-like proprotein convertase furin. The prototypic furin recognition cleavage site is Arg-X-Arg/Lys-Arg. Arg-Arg-Arg-Arg-Arg-Arg or longer iterations of polyarginine have been shown to be competitive inhibitors of substrate cleavage by furin. Here, we tested polyarginine for inhibition of productive human immunodeficiency virus-1-infection in T-cell lines, primary peripheral blood mononuclear cells, and macrophages. We found that polyarginine inhibited significantly human immunodeficiency virus-1 replication at concentrations that were benign to cell cultures ex vivo and mice in vivo. Using a fluorogenic assay, we demonstrated that polyarginine potently inhibited substrate-specific proteolytic cleavage by furin. Moreover, we verified that authentic processing of human immunodeficiency virus-1 gp160 synthesized in human cells from an infectious human immunodeficiency virus-1 (HIV-1) molecular clone was effectively blocked by polyarginine. Taken together, our data support that inhibitors of proteolytic processing of gp160 may be useful for combating human immunodeficiency virus-1 and that polyarginine represents a lead example of such inhibitors.


Received for publication, March 26, 2004 , and in revised form, September 7, 2004.

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

§ Both authors contributed equally to this study.

{ddagger}{ddagger} To whom correspondence should be addressed: Bldg. 4, Rm. 306, 9000 Rockville Pike, NIAID, National Institutes of Health, Bethesda, Maryland, 20892-0460. Tel.: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e{at}nih.gov.


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