With the U.S. Food and Drug Administration approval of raltegravir (RAL; MK-0518; Merck & Co.), HIV-1 integrase (IN) is the newest therapeutic target for AIDS and HIV infections. Recent structural analyses show that IN strand transfer inhibitors (INSTIs) share a common binding mode in the enzyme active site. While RAL represents a therapeutic breakthrough, the emergence of IN resistance mutations imposes the development of new INSTIs. We report here the biochemical and antiviral activities of MK-0536, a new IN inhibitor. We demonstrate that, like RAL, MK-0536 is highly potent against recombinant IN and viral replication. It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant. Modeling of IN developed from recent prototype foamy virus structures is presented to account for the differences in the drug activities of MK-0536 and RAL against the IN mutants.

中文翻译：

---

MK-0536 抑制对拉替拉韦耐药的 HIV-1 整合酶。

随着美国食品和药物管理局批准拉替拉韦 (RAL; MK-0518; Merck & Co.)，HIV-1 整合酶 (IN) 成为 AIDS 和 HIV 感染的最新治疗靶点。最近的结构分析表明，IN 链转移抑制剂 (INSTI) 在酶活性位点具有共同的结合模式。虽然 RAL 代表了治疗上的突破，但 IN 抗性突变的出现推动了新 INSTI 的发展。我们在此报告了新型 IN 抑制剂 MK-0536 的生化和抗病毒活性。我们证明，与 RAL 一样，MK-0536 对重组 IN 和病毒复制非常有效。它还对携带三个主要 RAL 抗性突变（Y143R、N155H 和在较小程度上 G140S-Q148H）和 G118R 突变体的 IN 有效。