1065478-18-3Relevant academic research and scientific papers
Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies
Vuong, Wayne,Fischer, Conrad,Khan, Muhammad Bashir,van Belkum, Marco J.,Lamer, Tess,Willoughby, Kurtis D.,Lu, Jimmy,Arutyunova, Elena,Joyce, Michael A.,Saffran, Holly A.,Shields, Justin A.,Young, Howard S.,Nieman, James A.,Tyrrell, D. Lorne,Lemieux, M. Joanne,Vederas, John C.
, (2021)
Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (Mpro) to cleave viral proteins. Consequently, Mpro is a target for antiviral agents. We and others previously demonstrated that GC376, a bisulfite prodrug with efficacy as an anti-coronaviral agent in animals, is an effective inhibitor of Mpro in SARS-CoV-2. Here, we report structure-activity studies of improved GC376 derivatives with nanomolar affinities and therapeutic indices >200. Crystallographic structures of inhibitor-Mpro complexes reveal that an alternative binding pocket in Mpro, S4, accommodates the P3 position. Alternative binding is induced by polar P3 groups or a nearby methyl. NMR and solubility studies with GC376 show that it exists as a mixture of stereoisomers and forms colloids in aqueous media at higher concentrations, a property not previously reported. Replacement of its Na+ counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for Mpro inhibitor design.
A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**
Yang, Kai S.,Ma, Xinyu R.,Ma, Yuying,Alugubelli, Yugendar R.,Scott, Danielle A.,Vatansever, Erol C.,Drelich, Aleksandra K.,Sankaran, Banumathi,Geng, Zhi Z.,Blankenship, Lauren R.,Ward, Hannah E.,Sheng, Yan J.,Hsu, Jason C.,Kratch, Kaci C.,Zhao, Baoyu,Hayatshahi, Hamed S.,Liu, Jin,Li, Pingwei,Fierke, Carol A.,Tseng, Chien-Te K.,Xu, Shiqing,Liu, Wenshe Ray
supporting information, p. 942 - 948 (2020/12/15)
The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital pr
Design, synthesis, and evaluation of 3C protease inhibitors as anti-enterovirus 71 agents
Kuo, Chih-Jung,Shie, Jiun-Jie,Fang, Jim-Min,Yen, Guei-Rung,Hsu, John T.-A.,Liu, Hun-Ge,Tseng, Sung-Nain,Chang, Shih-Cheng,Lee, Ching-Yin,Shih, Shin-Ru,Liang, Po-Huang
, p. 7388 - 7398 (2008/12/22)
Human enterovirus (EV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. A peptidomimetic inhibitor AG7088 was developed to inhibit the 3C protease of rhinovirus (a member of the family), a chymotrypsin-like protea
