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Journal of Virology, July 2006, p. 6883-6894, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00306-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dihydroxythiophenes Are Novel Potent Inhibitors of Human Immunodeficiency Virus Integrase with a Diketo Acid-Like Pharmacophore

S. Kehlenbeck,1 U. Betz,1 A. Birkmann,1 B. Fast,1 A. H. Göller,2 K. Henninger,3 T. Lowinger,2 D. Marrero,4 A. Paessens,1 D. Paulsen,1 V. Pevzner,1 R. Schohe-Loop,2 H. Tsujishita,5 R. Welker,1 J. Kreuter,6 H. Rübsamen-Waigmann,1 and F. Dittmer1*

Antiinfective Research, Virology,1 Chemical Research,2 Pharmacological Research, Pharma Research Center, Bayer HealthCare AG, D-42096 Wuppertal, Germany,3 IRT, Bayer Corp., Pharmaceutical Division, West Haven, Connecticut 06516-4175,4 Department of Chemistry, Research Center Kyoto, Bayer Yakuhin, J-619-0126, Kyoto, Japan,5 Institute for Pharmaceutical Technology, Johann Wolfgang Goethe-Universität, D-60439 Frankfurt/Main, Germany6

Received 12 February 2006/ Accepted 23 April 2006

We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.

* Corresponding author. Mailing address: Product-Related Research, Bayer HealthCare AG, Aprather Weg 18a, 42096 Wuppertal, Germany. Phone: 49-202-368361. Fax: 49-202-365149. E-mail: frank.dittmer{at}bayerhealthcare.com.

Journal of Virology, July 2006, p. 6883-6894, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00306-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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