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J. Biol. Chem., Vol. 282, Issue 39, 28709-28720, September 28, 2007

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Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization^*

Yasuhiro Koh, Shintaro Matsumi, Debananda Das^¶, Masayuki Amano, David A. Davis^||, Jianfeng Li^**, Sofiya Leschenko^**, Abigail Baldridge^**, Tatsuo Shioda, Robert Yarchoan^||, Arun K. Ghosh^**, and Hiroaki Mitsuya^¶1

From the Department of Hematology and Department of Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan, the ^¶Experimental Retrovirology Section and ^||Retroviral Disease Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, the ^**Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, and the Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Dimerization of HIV-1 protease subunits is essential for its proteolytic activity, which plays a critical role in HIV-1 replication. Hence, the inhibition of protease dimerization represents a unique target for potential intervention of HIV-1. We developed an intermolecular fluorescence resonance energy transfer-based HIV-1-expression assay employing cyan and yellow fluorescent protein-tagged protease monomers. Using this assay, we identified non-peptidyl small molecule inhibitors of protease dimerization. These inhibitors, including darunavir and two experimental protease inhibitors, blocked protease dimerization at concentrations of as low as 0.01 µM and blocked HIV-1 replication with IC₅₀ values of 0.0002-0.48 µM. These agents also inhibited the proteolytic activity of mature protease. Other approved anti-HIV-1 agents examined except tipranavir, a CCR5 inhibitor, and soluble CD4 failed to block the dimerization event. Once protease monomers dimerize to become mature protease, mature protease is not dissociated by this dimerization inhibition mechanism, suggesting that these agents block dimerization at the nascent stage of protease maturation. The proteolytic activity of mature protease that managed to undergo dimerization despite the presence of these agents is likely to be inhibited by the same agents acting as conventional protease inhibitors. Such a dual inhibition mechanism should lead to highly potent inhibition of HIV-1.

Received for publication, May 14, 2007 , and in revised form, June 25, 2007.

^* This work was supported by the Intramural Research Program of Center for Cancer Research, NCI, National Institutes of Health (NIH), by a Grant-in-aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu-Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan (Kosei-Rohdosho), by the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases (Renkei Jigyo: Grant 78, Kumamoto University) of Monbu-Kagakusho, by the Japan Health Sciences Foundation (International Research Grant SA14801 to H. M. and A. K. G.), and by NIH Grant GM 53386 (to A. K. G.). 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 To whom correspondence should be addressed: Tel.: 81-96-373-5156; Fax: 81-96-363-5265; E-mail: hmitsuya{at}helix.nih.gov.

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