Hui K Y, Hermann R B, Manetta J V, Gygi T, Angleton E L
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
FEBS Lett. 1993 Aug 2;327(3):355-60. doi: 10.1016/0014-5793(93)81020-z.
Through a series of synthetic model peptides, we have examined the structural requirements of the P2 and P3 residues in statine-based HIV protease (PR) inhibitors. Results agree with the general observations that, the more bulky the P3 aromatic hydrophobic side chain, the more potent is the inhibitor. At P2, an isopropyl side chain is critical in maintaining potency. Three-dimensional modeling demonstrates that the steric bulk of a leucyl residue or the unfavorable energy transfer, from water to enzyme, for a basic amino acid residue at P2 markedly compromises activity. A naphthylalaninyl-valyl P3-P2 substituted analogue inhibits PR with an IC50 value of 6 nM, and was also effective as an antiviral agent.
通过一系列合成模型肽，我们研究了基于他汀的HIV蛋白酶（PR）抑制剂中P2和P3残基的结构要求。结果与一般观察结果一致，即P3芳香族疏水侧链越大，抑制剂的效力越强。在P2位置，异丙基侧链对维持效力至关重要。三维建模表明，P2位置亮氨酰残基的空间体积或碱性氨基酸残基从水到酶的不利能量转移会显著损害活性。一种萘丙氨酰-缬氨酰P3-P2取代类似物抑制PR的IC50值为6 nM，并且作为抗病毒剂也有效。
