Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models

被引：95

作者：

Li, Yingjun ^{[1
,2
]}

Cao, Liu ^{[3
]}

Li, Ge ^{[4
]}

Cong, Feng ^{[4
]}

Li, Yunfeng ^{[4
]}

Sun, Jing ^{[5
]}

Luo, Yinzhu ^{[4
]}

Chen, Guijiang ^{[4
]}

Li, Guanguan ^{[1
]}

Wang, Ping ^{[1
]}

Xing, Fan ^{[3
]}

Ji, Yanxi ^{[3
]}

Zhao, Jincun ^{[5
]}

Zhang, Yu ^{[4
]}

Guo, Deyin ^{[3
]}

Zhang, Xumu ^{[1
,2
]}

机构：

[1] Southern Univ Sci & Technol, Coll Sci, Dept Chem, Shenzhen Key Lab Small Mol Drug Discovery & Synth, Shenzhen 518055, Guangdong, Peoples R China

[2] Southern Univ Sci & Technol, Acad Adv Interdisciplinary Studies, Medi X, Shenzhen 518055, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Ctr Infect & Immun Studies, Sch Med, Shenzhen 518107, Peoples R China

[4] Guangdong Lab Anim Monitoring Inst, Guangdong Prov Key Lab Lab Anim, Guangzhou 510663, Guangdong, Peoples R China

[5] Guangzhou Med Univ, Natl Clin Res Ctr Resp Dis, Guangzhou Inst Resp Hlth, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou 510182, Guangdong, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 04期

基金：

中国国家自然科学基金;

关键词：

ANTIVIRAL ACTIVITY; TISSUE-CULTURE; VIRUS; CORONAVIRUS; PRODRUG; MECHANISM; EFFICACY; GS-5734; EBOLA;

D O I：

10.1021/acs.jmedchem.0c01929

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

引用

页码：2785 / 2793

页数：9

共 50 条

[21] Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia
Siegrist, Denise
Jonsdottir, Hulda R.
Bouveret, Mendy
Boda, Bernadett
Constant, Samuel
Engler, Olivier B.
PHARMACEUTICS, 2024, 16 (10)
[22] Mouse Models for the Study of SARS-CoV-2 Infection
Knight, Audrey C.
Montgomery, Stephanie A.
Fletcher, Craig A.
Baxter, Victoria K.
COMPARATIVE MEDICINE, 2021, 71 (05) : 383 - 397
[23] First analytical confirmation of drug-induced crystal nephropathy in felines caused by GS-441524, the active metabolite of Remdesivir
Furbish, Amelia
Allinder, Marissa
Austin, Glenn
Tynan, Beth
Byrd, Emilee
Gomez, Ivette Pina
Peterson, Yuri
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2024, 247
[24] Population pharmacokinetic modeling of GS-441524, the active metabolite of remdesivir, in Japanese COVID-19 patients with renal dysfunction
Sukeishi, Asami
Itohara, Kotaro
Yonezawa, Atsushi
Sato, Yuki
Matsumura, Katsuyuki
Katada, Yoshiki
Nakagawa, Takayuki
Hamada, Satoshi
Tanabe, Naoya
Imoto, Eishi
Kai, Shinichi
Hirai, Toyohiro
Yanagita, Motoko
Ohtsuru, Shigeru
Terada, Tomohiro
Ito, Isao
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, 2022, 11 (01): : 94 - 103
[25] Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro
Brunotte, Linda
Zheng, Shuyu
Mecate-Zambrano, Angeles
Tang, Jing
Ludwig, Stephan
Rescher, Ursula
Schloer, Sebastian
PHARMACEUTICS, 2021, 13 (09)
[26] Artificial Neural Network-Based Study Predicts GS-441524 as a Potential Inhibitor of SARS-CoV-2 Activator Protein Furin: a Polypharmacology Approach
M. Dhanalakshmi
Kajari Das
Medha Pandya
Sejal Shah
Ayushman Gadnayak
Sushma Dave
Jayashankar Das
Applied Biochemistry and Biotechnology, 2022, 194 : 4511 - 4529
[27] Remdesivir experience in patients with severe SARS-COV-2 infection
Luque, Jesus Cotrina
Pereira, Catia
Rei, Maria Jose
Capoulas, Miriam
Santos, Claudia
INTERNATIONAL JOURNAL OF CLINICAL PHARMACY, 2021, 43 (06) : 1776 - 1776
[28] Artificial Neural Network-Based Study Predicts GS-441524 as a Potential Inhibitor of SARS-CoV-2 Activator Protein Furin: a Polypharmacology Approach
Dhanalakshmi, M.
Das, Kajari
Pandya, Medha
Shah, Sejal
Gadnayak, Ayushman
Dave, Sushma
Das, Jayashankar
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY, 2022, 194 (10) : 4511 - 4529
[29] Development and validation of a paper spray mass spectrometry method for the rapid quantitation of remdesivir and its active metabolite, GS-441524, in human plasma
Skaggs, Christine
Zimmerman, Hannah
Manicke, Nicholas
Kirkpatrick, Lindsey
JOURNAL OF MASS SPECTROMETRY AND ADVANCES IN THE CLINICAL LAB, 2022, 25 : 27 - 35
[30] Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice
Pruijssers, Andrea J.
George, Amelia S.
Schafer, Alexandra
Leist, Sarah R.
Gralinksi, Lisa E.
Dinnon, Kenneth H., III
Yount, Boyd L.
Agostini, Maria L.
Stevens, Laura J.
Chappell, James D.
Lu, Xiaotao
Hughes, Tia M.
Gully, Kendra
Martinez, David R.
Brown, Ariane J.
Graham, Rachel L.
Perry, Jason K.
Du Pont, Venice
Pitts, Jared
Ma, Bin
Babusis, Darius
Murakami, Eisuke
Feng, Joy Y.
Bilello, John P.
Porter, Danielle P.
Cihlar, Tomas
Baric, Ralph S.
Denison, Mark R.
Sheahan, Timothy P.
CELL REPORTS, 2020, 32 (03):

← 1 2 3 4 5 →