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J. Biol. Chem., Vol. 283, Issue 15, 9797-9804, April 11, 2008

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A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells^*

Catherine Coffinier¹², Sarah E. Hudon¹, Roger Lee, Emily A. Farber, Chika Nobumori, Jeffrey H. Miner^¶, Douglas A. Andres^||, H. Peter Spielmann^||, Christine A. Hrycyna, Loren G. Fong, and Stephen G. Young^**

From the Departments of Medicine and ^**Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, the Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, the ^¶Department of Internal Medicine, Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^||Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536

HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMPSTE24 and leads to an accumulation of prelamin A.

Received for publication, November 27, 2007 , and in revised form, January 24, 2008.

^* This work was supported by National Institutes of Health Grants AR050200, HL76839, CA099506 (to S. G. Y.), HL86683 (to L. F. G.), AR049469 (to J. H. M.) and GM66152 (to H. P. S.), grants from the Progeria Research Foundation (to S. G. Y. and L. G. F.), a grant from the Kentucky Lung Cancer Research Program (to H. P. S.), Beginning Grant-in-aid 0665016Y from the American Heart Association, Western States Affiliate (to C. C.), a grant from Bristol-Myers Squibb (to S. G. Y.), the UCLA Specialty Training & Advanced Research (STAR) Program, and the Dermatology Foundation (to R. L.). The authors have no relationship with the manufacturer of darunavir. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: 695 Charles E. Young Dr. South, Los Angeles, CA 90095. Tel.: 310-267-4380; Fax: 310-267-2722; E-mail: coffinie{at}ucla.edu.

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