Rossmann M G
Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
Antiviral Res. 1989 Feb;11(1):3-13. doi: 10.1016/0166-3542(89)90016-8.
The tertiary structure of most icosahedral viral capsid proteins consists of an eight-stranded antiparallel beta-barrel with a hydrophobic interior. In a group of picornaviruses, this hydrophobic pocket can be filled by suitable organic molecules, which stop viral uncoating after attachment and penetration into the host cell. The antiviral activity of these agents is probably due to increased rigidity of the capsid protein, thereby inhibiting disassembly. The hydrophobic pocket may be an essential functional component of the protein and may have been conserved in the evolution of many viruses from a common precursor. Since eight-stranded anti-parallel beta-barrels, with a topology as in viral capsid proteins, are not generally found in other proteins involved in cell metabolism, antiviral agents that bind in the interior of viral capsid proteins are likely to be more virus-specific and less cytotoxic. Furthermore, the greatest conservation of viral capsid proteins occurs within this pocket, whereas the least conserved part is the antigenic exterior. Thus, compounds that bind to such a pocket are likely to be effective against a broader group of serologically distinct viruses. Discovery of antiviral agents of this type depends on designing compounds that can enter and fit snugly into the hydrophobic pocket of a particular viral capsid protein.
大多数二十面体病毒衣壳蛋白的三级结构由一个具有疏水内部的八链反平行β桶组成。在一组小核糖核酸病毒中，这个疏水口袋可以被合适的有机分子填充，这些分子在病毒附着并侵入宿主细胞后阻止病毒脱壳。这些药物的抗病毒活性可能是由于衣壳蛋白的刚性增加，从而抑制了病毒的解体。疏水口袋可能是该蛋白的一个重要功能组件，并且可能在许多病毒从共同前体进化的过程中得以保留。由于具有与病毒衣壳蛋白相同拓扑结构的八链反平行β桶在参与细胞代谢的其他蛋白中一般不存在，因此结合在病毒衣壳蛋白内部的抗病毒药物可能更具病毒特异性且细胞毒性更小。此外，病毒衣壳蛋白的最大保守区域出现在这个口袋内，而最不保守的部分是抗原性外部。因此，与这样一个口袋结合的化合物可能对更广泛的血清学不同的病毒有效。这类抗病毒药物的发现取决于设计能够进入并紧密契合特定病毒衣壳蛋白疏水口袋的化合物。
