Ang Melgious J Y, Lau Qiu Ying, Ng Fui Mee, Then Siew Wen, Poulsen Anders, Cheong Yuen Kuen, Ngoh Zi Xian, Tan Yong Wah, Peng Jianhe, Keller Thomas H, Hill Jeffrey, Chu Justin J H, Chia C S Brian
a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
b Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) , Singapore , and.
J Enzyme Inhib Med Chem. 2016;31(2):332-9. doi: 10.3109/14756366.2015.1018245. Epub 2015 Sep 4.
Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 ± 0.4 versus 7.3 ± 0.8 μM). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities.
肠道病毒71型（EV71）是一种高传染性病原体，主要引发手足口病，尤其是在儿童中。目前，尚未开发出针对该疾病的获批抗病毒药物。EV71 3C蛋白酶因其在病毒多聚蛋白加工过程中的关键作用而被视为一个有吸引力的药物靶点。鲁平替韦是一种最初开发用于靶向人鼻病毒3C蛋白酶的肽类抑制剂，被发现可抑制EV71 3C蛋白酶。在本通讯中，我们报告了30种鲁平替韦类似物对EV71 3C蛋白酶的抑制活性。发现最有效的抑制剂，含有一个P2环约束苯丙氨酸类似物（化合物9），其效力比鲁平替韦高两倍（IC50值为3.4±0.4对7.3±0.8μM）。我们的研究结果表明，在基于肽的蛋白酶抑制剂中使用几何约束残基可能会增强其抑制活性。
