BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents
| Autor: | Pin-Fang Lin, Qi Guo, Carol Deminie, Brian Terry, Fred Djang, Brett S. Robinson, Richard J. Colonno, Yi-Fei Gong, David A. Stock, Keith Riccardi, Wade S. Blair |
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| Rok vydání: | 2000 |
| Předmět: |
Pyridines
Atazanavir Sulfate Gene Products gag Microbial Sensitivity Tests In Vitro Techniques Biology Antiviral Agents Amprenavir Zidovudine Indinavir medicine Humans HIV Protease Inhibitor Drug Interactions Pharmacology (medical) Protein Precursors Cells Cultured Pharmacology Stavudine virus diseases Blood Proteins HIV Protease Inhibitors Virology Drug Combinations Infectious Diseases Nelfinavir HIV-1 Reverse Transcriptase Inhibitors Ritonavir Oligopeptides Saquinavir medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 44:2093-2099 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.44.8.2093-2099.2000 |
| Popis: | BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC50) of 2.6 to 5.3 nM and an EC90of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23,000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations. |
| Databáze: | OpenAIRE |
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