Duke-NUS Graduate Medical School, Program in Emerging Infectious Diseases, 8 College Road, Singapore 169857, Singapore.
Antiviral Res. 2011 Oct;92(1):96-101. doi: 10.1016/j.antiviral.2011.07.002. Epub 2011 Jul 8.
A series of tripeptide aldehyde inhibitors were synthesized and their inhibitory effect against dengue virus type 2 (DENV2) and West Nile virus (WNV) NS3 protease was evaluated side by side with the aim to discover potent flaviviral protease inhibitors and to examine differences in specificity of the two proteases. The synthesized inhibitors feature a varied N-terminal cap group and side chain modifications of a P2-lysine residue. In general a much stronger inhibitory effect of the tripeptide inhibitors was observed toward WNV protease. The inhibitory concentrations against DENV2 protease were in the micromolar range while they were submicromolar against WNV. The data suggest that a P2-arginine shifts the specificity toward DENV2 protease while WNV protease favors a lysine in the P2 position. Peptides with an extended P2-lysine failed to inhibit DENV2 protease suggesting a size-constrained S2 pocket. Our results generally encourage the investigation of di- and tripeptide aldehydes as inhibitors of DENV and WNV protease.
一系列三肽醛抑制剂被合成，并对其抑制登革热病毒 2 型（DENV2）和西尼罗河病毒（WNV）NS3 蛋白酶的效果进行了评估，旨在发现有效的黄病毒蛋白酶抑制剂，并研究两种蛋白酶特异性的差异。所合成的抑制剂具有不同的 N 末端帽基团和 P2-赖氨酸残基的侧链修饰。一般来说，三肽抑制剂对 WNV 蛋白酶的抑制作用要强得多。对 DENV2 蛋白酶的抑制浓度在微摩尔范围内，而对 WNV 的抑制浓度则在亚微摩尔范围内。这些数据表明，P2-精氨酸将特异性转向 DENV2 蛋白酶，而 WNV 蛋白酶则偏爱 P2 位置的赖氨酸。带有扩展 P2-赖氨酸的肽未能抑制 DENV2 蛋白酶，这表明 S2 口袋受到空间限制。我们的结果普遍鼓励对二肽和三肽醛作为 DENV 和 WNV 蛋白酶抑制剂的研究。
