Tie Yunfeng, Kovalevsky Andrey Y, Boross Peter, Wang Yuan-Fang, Ghosh Arun K, Tozser Jozsef, Harrison Robert W, Weber Irene T
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
Proteins. 2007 Apr 1;67(1):232-42. doi: 10.1002/prot.21304.
Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for AIDS therapy, has been studied in complexes with PR and the variants PR(I) (84V) and PR(V) (82A) containing the single mutations I84V and V82A that provide resistance to all the clinical inhibitors. Atomic resolution crystal structures (0.97-1.25 A) of the SQV complexes were analyzed in comparison to the protease complexes with darunavir, a new drug that targets resistant HIV, in order to understand the molecular basis of drug resistance. PR(I) (84V) and PR(V) (82A) complexes were obtained in both the space groups P2(1)2(1)2 and P2(1)2(1)2(1), which provided experimental limits for the conformational flexibility. The SQV interactions with PR were very similar in the mutant complexes, consistent with the similar inhibition constants. The mutation from bigger to smaller amino acids allows more space to accommodate the large group at P1' of SQV, unlike the reduced interactions observed in darunavir complexes. The residues 79-82 have adjusted to accommodate the large hydrophobic groups of SQV, suggesting that these residues are intrinsically flexible and their conformation depends more on the nature of the inhibitor than on the mutations in this region. This analysis will assist with development of more effective antiviral inhibitors.
沙奎那韦（SQV）是首个被批准用于艾滋病治疗的抗HIV-1蛋白酶（PR）抑制剂，已对其与PR以及含有单突变I84V和V82A的变体PR(I)（84V）和PR(V)（82A）形成的复合物进行了研究，这些突变使病毒对所有临床抑制剂产生耐药性。为了理解耐药性的分子基础，将SQV复合物的原子分辨率晶体结构（0.97 - 1.25 Å）与蛋白酶和新型抗耐药HIV药物达芦那韦形成的复合物进行了比较分析。PR(I)（84V）和PR(V)（82A）复合物在空间群P2(1)2(1)2和P2(1)2(1)2(1)中均有获得，这为构象灵活性提供了实验限制。在突变体复合物中，SQV与PR的相互作用非常相似，这与相似的抑制常数一致。与达芦那韦复合物中观察到的相互作用减少不同，从较大氨基酸到较小氨基酸的突变使得有更多空间容纳SQV在P1'位的大基团。79 - 82位残基已进行了调整以容纳SQV的大疏水基团，这表明这些残基本质上具有灵活性，其构象更多地取决于抑制剂的性质而非该区域的突变。该分析将有助于开发更有效的抗病毒抑制剂。
