A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors.

Abstract

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.

• Authors: Zhijun Zhang, Wen Xu, Yung-Hyo Koh, Jae Hoon Shim, Jean-Luc Girardet, Li-Tain Yeh, Robert K Hamatake, Zhi Hong
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 2 Pg. 429-37 (Feb 2007) ISSN: 0066-4804 [Print] United States
• PMID: 17116677 (Publication Type: Journal Article)

Chemical References

• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• Reverse Transcriptase Inhibitors
• Triazoles
• VRX-480773
• efavirenz

Topics

• Administration, Oral
• Alkynes
• Animals
• Anti-HIV Agents (administration & dosage, therapeutic use)
• Benzoxazines (pharmacology)
• Cell Line
• Cyclopropanes
• Dogs
• Drug Resistance, Viral (genetics)
• HIV Infections (drug therapy, virology)
• HIV-1 (drug effects, genetics)
• Humans
• Mutation
• Reverse Transcriptase Inhibitors (administration & dosage, pharmacokinetics)
• Triazoles (pharmacology, therapeutic use)