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Antimicrobial Agents and Chemotherapy, February 2007, p. 429-437, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01032-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors{triangledown}

Zhijun Zhang,* Wen Xu, Yung-Hyo Koh, Jae Hoon Shim, Jean-Luc Girardet, Li-Tain Yeh, Robert K. Hamatake, and Zhi Hong

Drug Discovery, Valeant Research and Development, 3300 Hyland Avenue, Costa Mesa, California 92626

Received 17 August 2006/ Returned for modification 16 October 2006/ Accepted 3 November 2006

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.

* Corresponding author. Mailing address: Drug Discovery, Valeant Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626. Phone: (714) 545-0100. Fax: (714) 668-3141. E-mail: zzhang{at}valeant.com.

{triangledown} Published ahead of print on 20 November 2006.

Antimicrobial Agents and Chemotherapy, February 2007, p. 429-437, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01032-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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