Ala P J, Huston E E, Klabe R M, Jadhav P K, Lam P Y, Chang C H
Experimental Station, DuPont Pharmaceuticals, Wilmington, Delaware 19880, USA.
Biochemistry. 1998 Oct 27;37(43):15042-9. doi: 10.1021/bi980386e.
The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.
艾滋病毒抗逆转录病毒疗法的长期治疗益处仍受到耐药变异体的威胁。蛋白酶S1亚位点的突变是对许多艾滋病毒蛋白酶抑制剂（包括我们的第一代基于环脲的抑制剂DMP323和DMP450）敏感性丧失的主要原因。我们现在报告了三种活性位点突变蛋白酶V82F、I84V和V82F/I84V与XV638和SD146形成复合物的结构，XV638和SD146是DMP323的两种P2类似物，对野生型的效力高8倍，并且能够抑制多种耐药变异体[贾德哈夫，P.K.等人（1997年）《药物化学杂志》40卷，第181 - 191页]。XV638和SD146效力增加主要是由于P2 - S2相互作用增强：范德华接触增加30 - 40%，并且额外增加了两到四个氢键。此外，由于这些新的相互作用不会干扰蛋白酶中的其他亚位点，其P2取代基的大互补表面积似乎弥补了P1 - S1相互作用的损失，并降低了选择耐药变异体的可能性。
