Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

doi:10.1007/s11684-023-1037-3

Front. Med.

2023, Vol. 17

Issue (6) : 1068-1079 https://doi.org/10.1007/s11684-023-1037-3

Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

Qiuyu Cao^1,², Yi Ding^1,², Yu Xu^1,², Mian Li^1,², Ruizhi Zheng^1,², Zhujun Cao³, Weiqing Wang^1,², Yufang Bi^1,², Guang Ning^1,², Yiping Xu⁴(

), Ren Zhao⁵(

)

¹. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². Shanghai National Clinical Research Center for Metabolic Diseases, State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
³. Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
⁴. Clinical Trials Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
⁵. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

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Abstract

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir–ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir–ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir–ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China’s homegrown anti-COVID-19 drugs.

Keywords COVID-19 antiviral drugs mindeudesivir

Corresponding Author(s): Yiping Xu,Ren Zhao

Just Accepted Date: 08 December 2023 Online First Date: 29 December 2023 Issue Date: 06 February 2024

Cite this article:

Qiuyu Cao,Yi Ding,Yu Xu, et al. Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)[J]. Front. Med., 2023, 17(6): 1068-1079.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1037-3
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1068

Generic name (brand name)	Drug type	Target virus life cycle stage	Eligible patients	Status
RdRp inhibitors
Azvudine (FNC)	Small molecule (oral)	RNA synthesis	Adults who have moderate COVID-19	Conditional approval in China
Remdesivir (Veklury)	Small molecule (i.v.)	RNA synthesis	Adults and children (28 days of age and older), weighing at least 3 kg, who are hospitalized or not and have mild-to-moderate COVID-19, are within 7 days of symptom onset, and are at high risk for severe COVID-19	Approved by the United States FDA, EUA in many countries, not approved in China
Molnupiravir (Lagevrio)	Small molecule (oral)	RNA synthesis	Adults who have mild-to-moderate COVID-19, are within 5 days of symptom onset, are at high risk for severe COVID-19, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate	Approved in UK, EUA in many countries, conditional approval in China
Mindeudesivir (Mindewei, VV116)	Small molecule (oral)	RNA synthesis	Adults who have mild-to-moderate COVID-19 at high risk for progression to severe COVID-19	EUA in Uzbekistan, conditional approval in China
Faripiravir (Favivir)	Small molecule (oral)	RNA synthesis	Adults who have mild-to-moderate COVID-19	Approved in India, not approved in China
M^pro inhibitors
Nirmatrelvir–ritonavir (Paxlovid)	Small molecule (oral)	Proteolytic processing	Adults and children (12 years and older) who have mild-to-moderate COVID-19, are within 5 days of symptom onset, and have one or more risk factors for severe COVID-19	Approved in UK and the United States, EUA in many countries, conditional approval in China
Simnotrelvir–ritonavir (Xiannuoxin)	Small molecule (oral)	Proteolytic processing	Adults who have mild-to-moderate COVID-19 and are within 3 days of symptom onset	Conditional approval in China
Leritrelvir	Small molecule (oral)	Proteolytic processing	Adults who have mild-to-moderate COVID-19 and are better off receiving treatment within 2 days of symptom onset	Conditional approval in China

Tab.1 Small-molecule anti-SARS-CoV-2 drugs for the management of COVID-19

Fig.1 Life cycle of SARS-CoV-2 in host cells and the mechanism of action for small-molecule antiviral drugs. The life cycle of SARS-CoV-2 in host cells includes: (1) viral entry through the interaction between the viral S protein and the cellular receptor angiotensin-converting enzyme 2 (ACE2); (2) viral genome release and translation into the viral replicase polyproteins; (3) viral protease cleavage; (4) viral genome replication mediated by the viral replication complex, including the RNA-dependent RNA polymerase (RdRp); (5) packaging of viral genomes and translation of viral structural proteins to assemble viral nucleocapsids; (6) virion release through exocytosis. Current small-molecule antiviral drugs function as either viral protease inhibitors to inhibit viral/endosome membrane fusion or viral polypeptide maturation (nirmatrelvir, simnotrelvir, leritrelvir), or nucleoside/nucleotide analogs to inhibit viral genome replication (remdesivir, molnupiravir, azvudine, mindeudesivir). Reprinted with permission from the reference [16]. Copyright 2020 American Chemical Society.

Fig.2 Chemical structures of M^pro inhibitors nirmatrelvir, simnotrelvir, and leritrelvir. (A) Chemical structure of nirmatrelvir (reprinted from the reference [29] under the terms of the Creative Commons Attribution License). (B) Chemical structure of simnotrelvir (reprinted with permission from ACS Pharmacol. Transl. Sci. 2023, 6, 9, 1306–1309. Copyright 2023 American Chemical Society). (C) Chemical structure of leritrelvir (reprinted from the reference [45] under the terms of the Creative Commons Attribution License).

Fig.3 Chemical structure of GS-441524 derivative mindeudesivir (VV116). Mindeudesivir (VV116) is a hydrobromide of the tri-isobutyrate ester prodrug of the 7-deuterated GS-441524 analog (X1). Reprinted from the reference [47] under the terms of the Creative Commons Attribution License.

Tab.2 Ongoing and completed clinical studies of mindeudesivir (based on a systematic search of ClinicalTrials.gov (accessed May 5, 2023))

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