NEW YORK (Reuters Health) - UIC-94017 (TMC114), a novel nonpeptidic HIV-1 protease inhibitor (PI), exerts “extremely potent” antiviral activity against laboratory HIV-1 strains and primary clinical isolates with minimal cytotoxicity, research suggests.
TMC114, which contains a bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isotere, has shown promise in phase II clinical trials (See Reuters Health reports Feb. 11 and July 16, 2003). The current report on TMC114, in the October issue of Antimicrobial Agents and Chemotherapy, represents “the first results of antiviral analyses,” according to Japanese and US researchers.
TMC114 efficiently blocked the infectivity and replication of HIV-1 variants resistant to saquinavir, indinavir, nelfinavir, or ritonavir, Dr. Yasuhiro Koh from Kumamoto University and colleagues report, although it was less active against amprenavir-resistant isolates.
TMC114 also demonstrated potent activity against multi-PI-resistant primary clinical HIV-1 variants isolated from patients who failed to respond to existing antiviral agents.
Structural analyses suggest that what makes TMC114 so active against PI-resistant HIV-1 variants is its close contact with the main chains of the protease active-site amino acids, Asp-29 and Asp-30, not the side chains with which other PIs interact.
“The issue of the emergence of drug-resistant HIV-1 variants is one of the most formidable challenges in the era of HAART,” Dr. Koh and colleagues write.
The current in vitro data coupled with early clinical data with TMC114 warrant continued development of this compound as a potential treatment for primary and multi-PI-resistant HIV-1 infections, they conclude.
Source: Antimicrob Agents Chemother 2003;47:3123-3129. [ Google search on this article ]
MeSH Headings:Enzyme Inhibitors: Enzymes, Coenzymes, and Enzyme Inhibitors: Protease Inhibitors: HIV Protease Inhibitors: Anti-HIV Agents: Anti-HIV Agents: Chemical Actions and Uses: Chemical Actions: Chemicals and Drugs: Chemicals and DrugsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
