Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor
| Autor: | Jeffrey H. Tidwell, George Andrew Freeman, Marty St. Clair, Robert G. Ferris, Lee T. Schaller, Dean W. Selleseth, Steven A. Short, Jill R. Cowan, Lawrence R. Boone, Kurt Weaver, G B Roberts, Joseph H. Chan, Richard J. Hazen, Kelly R. Moniri, Karen Rene Romines |
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| Rok vydání: | 2005 |
| Předmět: |
Anti-HIV Agents
Mutant Cell Culture Techniques Drug Evaluation Preclinical Biology Virus Replication Antiviral Agents Virus HeLa Benzophenones Inhibitory Concentration 50 Jurkat Cells Serial passage Cell Line Tumor Drug Resistance Viral medicine Humans Pharmacology (medical) Cytotoxicity Cells Cultured Serum Albumin Pharmacology Molecular Structure Reverse-transcriptase inhibitor Orosomucoid U937 Cells Prodrug Cytotoxicity Tests Immunologic biology.organism_classification Virology Reverse transcriptase Infectious Diseases Mutation HIV-1 Leukocytes Mononuclear Reverse Transcriptase Inhibitors HeLa Cells medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 49:4046-4051 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC 50 s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC 50 of ≤21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC 50 of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml α-1 acid glycoprotein increased the IC 50 approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents. |
| Databáze: | OpenAIRE |
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