The Body Covers: The 10th Conference on Retroviruses and Opportunistic Infections
In-Vitro Characterization of Novel Benzophenone NNRTIs
February 11, 2003
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) -- especially efavirenz (EFV, Sustiva) and nevirapine (NVP, Viramune) -- are widely used both in treatments for naïve and experienced patients, as they are highly potent and well tolerated. However, there are relatively few agents in this class compared with NRTIs and protease inhibitors, and the research pipeline has been somewhat unproductive due to widespread cross resistance within the class, toxicity, and formulation problems. The K103N mutation is a particular problem, as it emerges rapidly in treatment failure in NNRTI treated patients. This preclinical summary of a drug development program by GlaxoSmithKline described a new class of NNRTIs -- benzophenones -- that has activity against K103N mutants.
Three candidate compounds and their chemical structure were reviewed, GW4751, GW4511, and GW3011. All three showed both potent activity against wild-type strains as well as laboratory isolates with a wide range of NNRTI mutations, including K103N and Y181C. The addition of human serum to elaborate potential reduction in activity due to protein binding did impair activity somewhat, but to a lesser degree than with EFV. Cytotoxicity was low both in cell culture and in human bone marrow progenitor cells. The serial passage of virus in the presence of increasing concentrations of these agents selected for mutational changes at V106A, E138K, and F227L. The first of these (V106A) is likely to be the most important, and this mutation reduced activity of the drugs in vitro
To conclude, these are promising new NNRTIs active against wild type and commonly encountered NNRTI resistant viruses. As the number of patients with a history of virologic failure to NVP and EFV increases, a new drug in this class would be extremely valuable and greatly expand options for therapy.
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