raltegravir (free base) API

タイトルまたは説明

Raltegravir (MK****8) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E*2Q, G**0S Q**8H, N**5H, and E**7Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3' processing and strand transfer activities were moderately affected in the E*2Q mutant; strand transfer was markedly impaired in the N**5H mutant; both activities were strongly impaired in the G**0S Q**8H mutant; and the E**7Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E*2Q and G**0S Q**8H profiles were each associated with a *- to *-fold decrease in sensitivity, and the N**5H mutant was more than **-fold less sensitive to raltegravir. At least four genetic profiles (E*2Q, G**0S Q**8H, N**5H, and E**7Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3' processing was also impaired.