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Originally published In Press as doi:10.1074/jbc.M105670200 on July 13, 2001

J. Biol. Chem., Vol. 276, Issue 37, 35194-35200, September 14, 2001
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Novel Low Molecular Weight Spirodiketopiperazine Derivatives Potently Inhibit R5 HIV-1 Infection through Their Antagonistic Effects on CCR5*

Kenji MaedaDagger , Kazuhisa YoshimuraDagger , Shiro Shibayama§, Hiromu Habashita, Hideaki Tada§, Kenji Sagawa§, Toshikazu MiyakawaDagger , Manabu AokiDagger , Daikichi Fukushima§, and Hiroaki MitsuyaDagger ||**

From the Dagger  Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan, the § Exploratory Research Laboratories and  Department of Medicinal Chemistry, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan, and the || Experimental Retrovirology Section, Medicine Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892

Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (Mr 484) specifically blocked the binding of macrophage inflammatory protein-1alpha (MIP-1alpha ) to CCR5 (IC50 0.002 µM) and MIP-1alpha -elicited cellular Ca2+ mobilization (IC50 ~ 0.02 µM). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/macrophage tropic (R5) HIV-1 at IC50 values of 0.03 to 0.06 µM. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection.

* This work was supported in part by Research for the Future Program Grant JSPS-RFTF 97L00705 of the Japan Society for the Promotion of Science, a Grant-in-aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu-Kagakusho), and a Grant for Promotion of AIDS Research from the Ministry of Health Welfare and Labor of Japan (Kosei-Rohdosho).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.

** To whom correspondence should be addressed: Dept. of Internal Medicine II, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-0811, Japan. Tel.: 81-96-373-5156; Fax: 81-96-363-5265; E-mail: hmitsuya@helix.nih.gov.

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