Sham H L, Kempf D J, Molla A, Marsh K C, Kumar G N, Chen C M, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman G R, Sun E, Japour A J, Leonard J M, Plattner J J, Norbeck D W
Departments of Infectious Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Antimicrob Agents Chemother. 1998 Dec;42(12):3218-24. doi: 10.1128/AAC.42.12.3218.
The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.
人类免疫缺陷病毒（HIV）蛋白酶活性位点的第82位缬氨酸（Val 82）会因使用蛋白酶抑制剂利托那韦进行治疗而发生突变。通过利用HIV蛋白酶与利托那韦复合物的X射线晶体结构，设计出了与Val 82相互作用减弱的强效蛋白酶抑制剂ABT - 378。ABT - 378能有效抑制野生型和突变型HIV蛋白酶（抑制常数Ki = 1.3至3.6皮摩尔），阻断1型HIV实验室菌株和临床菌株的复制（50%有效浓度[EC50]，0.006至0.017微摩尔），并对体内经利托那韦筛选出的突变型HIV保持高效力（EC50，≤0.06微摩尔）。在体外，利托那韦能强烈抑制ABT - 378的代谢。因此，ABT - 378与利托那韦同时口服给药后，大鼠、犬和猴血浆中ABT - 378的浓度在8小时后超过人血清存在时的体外抗病毒EC50达50倍以上。在健康人类志愿者中，单次给予400毫克ABT - 378与50毫克利托那韦共同给药后，ABT - 378在血浆中的浓度曲线下面积比单独给予ABT - 378后观察到的值增加了77倍，且ABT - 378的平均浓度超过EC50达24小时以上。这些结果证明了ABT - 378作为抗艾滋病治疗干预手段的潜在效用。
