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J. Biol. Chem., Vol. 282, Issue 29, 20847-20853, July 20, 2007

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Targeting Host Cell Furin Proprotein Convertases as a Therapeutic Strategy against Bacterial Toxins and Viral Pathogens^*

Sergey A. Shiryaev¹, Albert G. Remacle¹, Boris I. Ratnikov¹, Nicholas A. Nelson, Alexei Y. Savinov, Ge Wei, Massimo Bottini, Michele F. Rega, Amelie Parent^¶, Roxane Desjardins^¶, Martin Fugere^¶, Robert Day^¶, Mojgan Sabet^||, Maurizio Pellecchia, Robert C. Liddington, Jeffrey W. Smith, Tomas Mustelin, Donald G. Guiney^||, Michal Lebl, and Alex Y. Strongin²

From the Burnham Institute for Medical Research, La Jolla, California 92037, Illumina, Inc., San Diego, California 92121, the Department of Pharmacology, ^¶University of Sherbrooke, Sherbrooke, Quebec, Canada J1H SN4, and the ^||Department of Medicine, School of Medicine, University of California-San Diego, La Jolla, California 92093

Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKRGL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1' were more selective for furin. Peptides with P1' Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.

Received for publication, May 10, 2007 , and in revised form, May 25, 2007.

^* This work was supported by National Institutes of Health Grants AI056385, AI061139, and RR020843 (to A. Y. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-6271; Fax: 858-646-3192; E-mail: strongin{at}burnham.org.

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