Grant R A, Hiremath C N, Filman D J, Syed R, Andries K, Hogle J M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Curr Biol. 1994 Sep 1;4(9):784-97. doi: 10.1016/s0960-9822(00)00176-7.
Picornaviruses, such as the structurally related polioviruses and rhinoviruses, are important human pathogens which have been the target of major drug development efforts. Receptor-mediated uncoating and thermal inactivation of poliovirus and rhinovirus are inhibited by agents that bind to each virus by inserting into a pocket in the beta barrel of the viral capsid protein, VP1. This pocket, which is normally empty in human rhinovirus-14 (HRV14), is occupied by an unknown natural ligand in poliovirus. Structural studies of HRV14-drug complexes have shown that drug binding causes large, localized changes in the conformation of VP1.
We report the crystal structures of six complexes between poliovirus and capsid-binding, antiviral drugs, including complexes of four different drugs with the Sabin vaccine strain of type 3 poliovirus, and complexes of one of these drugs with two other poliovirus strains that contain sequence differences in the drug-binding site. In each complex, the changes in capsid structure associated with drug binding are limited to minor adjustments in the conformations of a few side chains lining the binding site.
The minor structural changes caused by drug binding suggest a model of drug action in which it is the conformational changes prevented by the bound drug, rather than obvious conformational changes induced by drug binding, which exert the biological effect. Our results, along with additional structures of rhinovirus-drug complexes, suggest possible improvements in drug design, and provide important clues about the nature of the conformational changes that are involved in the uncoating process.
微小核糖核酸病毒，如结构相关的脊髓灰质炎病毒和鼻病毒，是重要的人类病原体，一直是主要药物研发工作的目标。脊髓灰质炎病毒和鼻病毒的受体介导的脱壳和热失活受到通过插入病毒衣壳蛋白VP1的β桶中的口袋与每种病毒结合的试剂的抑制。这个口袋在人鼻病毒14（HRV14）中通常是空的，在脊髓灰质炎病毒中被一种未知的天然配体占据。HRV14-药物复合物的结构研究表明，药物结合会导致VP1构象发生大的局部变化。
我们报告了脊髓灰质炎病毒与衣壳结合的抗病毒药物之间六种复合物的晶体结构，包括四种不同药物与3型脊髓灰质炎病毒Sabin疫苗株的复合物，以及其中一种药物与另外两种在药物结合位点含有序列差异的脊髓灰质炎病毒株的复合物。在每个复合物中，与药物结合相关的衣壳结构变化仅限于结合位点内衬的少数侧链构象的微小调整。
药物结合引起的微小结构变化提示了一种药物作用模型，即发挥生物学效应的是被结合药物阻止的构象变化，而不是药物结合诱导的明显构象变化。我们的结果，连同鼻病毒-药物复合物的其他结构，提示了药物设计可能的改进，并提供了关于脱壳过程中涉及的构象变化性质的重要线索。
