Abstract
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.
References
Apr 20, 1967·Biochemical and Biophysical Research Communications·I Schechter, A Berger
Nov 5, 1997·Analytical Biochemistry·Q M WangR J Loncharich
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·D A MatthewsS T Worland
Oct 3, 1999·Antimicrobial Agents and Chemotherapy·A K PatickS T Worland
May 15, 2002·FEMS Microbiology Reviews·Peter C McMinn
Jan 28, 2005·Antimicrobial Agents and Chemotherapy·S L BinfordA K Patick
Oct 6, 2005·Nature Reviews. Microbiology·J Lindsay WhittonRalph Feuer
May 6, 2006·Antiviral Research·Amy K Patick
Jun 28, 2008·Bioorganic & Medicinal Chemistry·Chih-Jung KuoPo-Huang Liang
May 15, 2009·Journal of Clinical Microbiology·Fan YangJin Qi
Oct 27, 2010·Drug Discovery Today·Kan X WuJustin J H Chu
Jan 18, 2011·Antiviral Research·Heléne NorderRolf Hilgenfeld
Jan 22, 2011·Virology·Ross E RhoadesRalph Feuer
Jul 29, 2011·Journal of Virology·Guangwen LuGeorge F Gao
Aug 5, 2011·Journal of Virology·Jing WangSheng Cui
Dec 25, 2012·Antiviral Research·Luqing ShangZheng Yin
Jan 9, 2013·Antiviral Research·Xiaonan ZhangZhenghong Yuan
Jan 17, 2013·ChemMedChem·Christian B M Poulie, Lennart Bunch
Citations
Oct 25, 2016·European Journal of Medicinal Chemistry·Guang-Hui MaXu Shen
Sep 21, 2016·Scientific Reports·Yong Wah TanJustin Jang Hann Chu
Jun 8, 2018·Chemical Biology & Drug Design·Quandeng NieLuqing Shang
Sep 9, 2017·Expert Opinion on Therapeutic Patents·Hyemin LeeSung-Hoon Kim
Mar 14, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yixuan WangZhuorong Li