Important note: Information in this article was accurate in July 2001. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, July 9, 2001
Michael Greer, Staff Medical Writer
NewsRx - Modified versions of the HIV drug foscarnet are effective against drug-resistance viral variants and can even reverse the effects of some resistance-conferring mutations, researchers in the United States report.
"Phosphonoformate (foscarnet; PFA) is a potent inhibitor of [HIV 1] reverse transcriptase (RT), but its use for the treatment of HIV 1 infection is limited by toxicity and the lack of an orally bioavailable formulation," explained Dr. John W. Mellors and colleagues at University of Pittsburgh and the University of California.
Mellors and coworkers found that some foscarnet prodrugs were more potent inhibitors of HIV replication than the original and could induce mutations that erased resistance to the commonly used antiretroviral drug zidovudine (AZT).
Alkylglycerol-conjugated foscarnet prodrugs were effective against a number of nucleoside-resistant HIV strains, they said. Even strains with the T69S [SA] insertion or Q151M complex, which confer high-level resistance to virtually all nucleoside RT inhibitors, were susceptible to the foscarnet prodrugs examined. These drugs were also effective when administered orally in mice, unlike unmodified foscarnet, Mellors and team noted.
After a number of serial passages, HIV strains resistant to foscarnet prodrugs were seen bearing some previously unseen mutations. Some of these novel mutations, including S117T and F160Y, reversed AZT resistance when selected for in resistant strains, study data showed.
The foscarnet prodrugs studied had sn-2 substituents of hydrogen, methyl, or ethyl ("Alkylglycerol prodrugs of phosphonoformate are potent in vitro inhibitors of nucleoside-resistant human immunodeficiency virus type 1 and select for resistance mutations that suppress zidovudine resistance," Antimicrobial Agents and Chemotherapy, June 2001;45(6):1621-1628).
"This suppression of AZT resistance is consistent with the effects of other foscarnet resistance mutations that reduce ATP-dependent removal of AZT monophosphate from terminated template primers," Mellors and colleagues concluded. "The favorable activity and resistance profiles of these PFA prodrugs warrant their further evaluation as clinical candidates."
The corresponding author for this report is John W. Mellors, University of Pittsburgh School of Medicine, 818 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261, USA. E-mail: mellors@msx.dept-med.pitt.edu.
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Key points reported in this study include:
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