Tibotec BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
Antimicrob Agents Chemother. 2011 Dec;55(12):5723-31. doi: 10.1128/AAC.00748-11. Epub 2011 Sep 6.
TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC(50)], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC(50), >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC(50) was ≤ 4 for 82% of isolates and ≤ 10 for 96% of isolates. The FC in TMC310911 EC(50) was ≤ 4 and ≤ 10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively. In vitro resistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC(50) = 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC(50) = 258). The activity against a comprehensive panel of PI-resistant mutants and the limited in vitro selection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.
TMC310911 是一种新型的人类免疫缺陷病毒 1 型（HIV-1）蛋白酶抑制剂（PI），与达芦那韦（DRV）结构上密切相关，但具有改善的病毒学特征。TMC310911 对野生型（WT）HIV-1 具有强大的活性（中位数 50%有效浓度 [EC50]，14 nM），并对广泛的重组 HIV-1 临床分离株具有广谱活性，包括对目前批准的 PI 敏感性降低的多种 PI 耐药株（EC50 的折叠变化 [FC]，>10）。对于一组对至少一种目前批准的 PI 敏感性降低的 2011 个重组临床分离株，TMC310911 EC50 的 FC 对于 82%的分离株≤4，对于 96%的分离株≤10。对于对 DRV 敏感性降低的分离株，TMC310911 EC50 的 FC 分别对于 72%和 94%的分离株≤4 和≤10。用 WT 病毒和 TMC310911 进行的体外耐药选择（IVRS）实验选择了 R41G 或 R41E 突变，但耐药病毒的选择需要比用 WT 病毒和 DRV 进行的 IVRS 更长的时间。用 r13025（一种多种 PI 耐药的重组临床分离株）和 TMC310911 进行的 IVRS 选择了 L10F、I47V 和 L90M 突变（TMC310911 EC50 的 FC=16）。在 DRV 存在的情况下用 r13025 进行的 IVRS 需要更少的时间，并导致更多的 PI 耐药相关突变（V32I、I50V、G73S、L76V 和 V82I；DRV EC50 的 FC=258）。对广泛的 PI 耐药突变体的活性和药物压力下耐药病毒的有限体外选择表明，TMC310911 代表了一种治疗广泛患者（包括多种 PI 耐药患者）HIV-1 感染的潜在候选药物。
