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SM Journal of Infectious Diseases

Discovery of GST-HG171, A Potent and Selective Oral 3CL Protease Inhibitor for the Treatment of COVID-19

[ ISSN : 3066-134X ]

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Received: 19-Aug-2023

Accepted: 31-Aug-2023

Published: 02-Sep-2023

Research Article | Volume 6 - Issue 1 | Article DOI :

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George Zhang¹#, John Mao¹#, Haiying He⁶#, Ke Xu²#, Jing Zhou⁴, Yaxun Yang⁶, Peng Li⁶, Yong Du¹, Hong Zhang⁴, Shikui Chen¹, Wenwen Lei², Yunlong Lin⁵, Hong Chen⁴, Zheng Wang⁶, Yanan Tang¹, Wenhao Yan¹, Xiangyu Yang⁵, Zhengyu Liang³, Juan Li⁸, Shilong Zhu⁸, Tianxiang Zhang¹, Chuanjing Li¹, Jiarong Lin¹, Xiuping Yan¹, Hongshan Tan¹, Hongming Li¹, Guoping Li¹, Haijun Fu⁸, Wenfang Yuan⁹, Xiaochun Chen⁷, Zifeng Yang³, Xinwen Chen³, Yanhua Ding⁴, Shuhui Chen⁶, Hongzhou Lu⁵, Guizhen Wu², and Nanshan Zhong³

¹Fujian Akeylink Biotechnology Co., Ltd., /Fujian Cosunter Pharmaceutical Co., Ltd., Fuzhou, Fujian, China

²National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

³State Key Laboratory of Respiratory Disease Guangzhou, Guangdong, China

?The First Hospital of Jilin University, Jilin, China

?The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China

?WuXi AppTec Shanghai Co. Ltd., Shanghai, China

?Fujian Medical University, Fujian, China

?Shanghai Zenith Medical Research Co., Ltd., Shanghai, China

?Shijiazhuang Fifth Hospital, Shijiazhuang, China

#These authors contributed equally to this work

Corresponding Author:

1 George Zhang, Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China 6 Shuhui Chen, WuXi AppTec Shanghai Co. Ltd., Shanghai, China 5 Hongzhou Lu, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China 2 Guizhen Wu, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

Abstract

The coronavirus 3C-Like (3CL) protease, aka Main protease (Mpro), has become a clinically validated therapeutic target for developing new COVID-19 therapeutics with the recent success of Paxlovid (nirmatrelvir/ritonavir) in treating high-risk COVID-19 patients in clinic. However, there is still a huge unmet medical need for effective drugs for treating COVID-19 patients with standard-risk as well as those who experience rebounds after Paxlovid treatment. Here we report the discovery of a novel 3CL protease inhibitor, GST-HG171 that is more potent and effective than nirmatrelvir in pre-clinical studies both in vitro and in vivo. GST-HG171 has broad-spectrum activity against different variants of SARS-CoV-2, including Beta, Delta, Omicron B.1.1.529, Omicron BA.4, BA.5 variants with 5-10 fold higher potency than nirmatrelvir when tested head-to-head in cytopathic effect assay. In vivo, GST-HG171 demonstrated higher efficacy than nirmatrelvir in reducing the viral load of lung tissue in mice infected with SARS-CoV-2 virus. Furthermore, GST-HG171 has demonstrated a more preferable lung tissue distribution in rats than nirmatrelvir, with a 4-5 fold higher lung/plasma exposure ratio. Finally GST-HG171 has an excellent safety profile in both pre-clinical studies and Ph1 clinical study in healthy human volunteers. In a Single Ascending Dose (SAD) Ph1 clinical trial, GST-HG171 demonstrated a dose-proportional increase in Cmax and exposure up to 600 mg. At 600 mg, GST-HG171 has an exposure of 23166 h*ng/mL, which is 4.2-fold higher than that reported for nirmatrelvir at a similar dose (5465 h*ng/mL at 500 mg). In sum, GST-HG171 is a novel, safe and more potent 3CL protease inhibitor than nirmatrelvir, and has the potential to become a superior broad-spectrum and effective COVID-19 therapeutic. Currently, GST-HG171 is under investigation in a large Ph3 trial in mild and moderate COVID-19 patients in China.

Citation

Zhang G, Mao J, He H, Xu K, Zhou J, et al. (2023) Discovery of GST-HG171, A Potent and Selective Oral 3CL Protease Inhibitor for the Treatment of COVID-19. SM J Infect Dis 6: 9.