The SARS-CoV-2 Cytopathic Effect Is Blocked by Lysosome Alkalizing Small Molecules.

ACS Infectious Diseases
Kirill GorshkovWei Zheng

Abstract

Understanding the SARS-CoV-2 virus' pathways of infection, virus-host-protein interactions, and mechanisms of virus-induced cytopathic effects will greatly aid in the discovery and design of new therapeutics to treat COVID-19. Chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including alkalizing lysosomes and blocking autophagy as well as exhibiting dose-limiting toxicities in patients. Therefore, we evaluated additional lysosomotropic compounds to identify an alternative lysosome-based drug repurposing opportunity. We found that six of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero E6 cells with half-maximal effective concentration (EC50) values ranging from 2.0 to 13 μM and selectivity indices (SIs; SI = CC50/EC50) ranging from 1.5- to >10-fold. The compounds (1) blocked lysosome functioning and autophagy, (2) prevented pseudotyped particle entry, (3) increased lysosomal pH, and (4) reduced (ROC-325) viral titers in the EpiAirway 3D tissue model. Consistent with these findings, the siRNA knockdown of ATP6V0D1 blocked the HCoV-NL63 cytopathic effect in LLC-MK2 cells. Moreover, an analysis of SARS-CoV-2 infected Vero E6 cell lysate reve...Continue Reading

References

Jun 1, 1991·Clinical Pharmacokinetics·A E Balant-GorgiaL P Balant
Jul 1, 1990·DICP : the Annals of Pharmacotherapy·M W Kelly, C W Myers
Mar 1, 1987·The American Journal of Tropical Medicine and Hygiene·D J Krogstad, P H Schlesinger
Aug 1, 1988·Clinical Pharmacokinetics·G Edwards, A M Breckenridge
Sep 1, 1967·Journal of Medicinal Chemistry·D RosiS Archer
Jan 1, 1981·Methods in Enzymology·P C FamillettiS Pestka
Oct 1, 1996·Clinical Pharmacokinetics·J Ducharme, R Farinotti
Apr 1, 1996·Clinical Pharmacokinetics·S Krishna, N J White
Nov 13, 1998·Biologicals : Journal of the International Association of Biological Standardization·A J DarlingJ Spaltro
Feb 7, 2001·Journal of Medical Microbiology·D F FerreiraM C Rebello
Nov 18, 2000·Molecular Therapy : the Journal of the American Society of Gene Therapy·P Shabram, E Aguilar-Cordova
Nov 1, 2003·The Lancet Infectious Diseases·Andrea SavarinoRoberto Cauda
Dec 3, 2003·The Journal of General Virology·M-L NgA-E Ling
Jan 28, 2006·The Lancet Infectious Diseases·Andrea SavarinoAntonio Cassone
Jun 6, 2009·JALA : Journal of the Association for Laboratory Automation·Clinton B MaddoxE Lucile White
Jun 10, 2009·Antimicrobial Agents and Chemotherapy·Els KeyaertsPiet Maes
Feb 11, 2010·Cell·Noboru MizushimaBeth Levine
Aug 12, 2010·Methods in Molecular Biology·Isei Tanida, Satoshi Waguri
Dec 15, 2010·The Journal of Biological Chemistry·Jennifer S CarewSteffan T Nawrocki
Jan 5, 2011·The Journal of Biological Chemistry·Elizabeth DonohueMichel Roberge
Jan 26, 2011·Cancer Biology & Therapy·Zhineng J YangFrank Sinicrope
Apr 3, 2012·Neuroscience Letters·Ji Hyun ShinDong-Hyung Cho
Jul 6, 2014·Autophagy·Eleanor M CottamThomas Wileman
Nov 25, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jennifer S CarewSteffan T Nawrocki
Jan 25, 2017·Autophagy·Jennifer S Carew, Steffan T Nawrocki
Nov 19, 2017·Scientific Reports·Sergey A ShiryaevAlexey V Terskikh
Nov 28, 2017·Antiviral Research·Yong Wah TanJustin Jang Hann Chu
Sep 7, 2018·Cell Death & Disease·Yuan YueJohn H Kehrl
Mar 19, 2019·Journal of Visualized Experiments : JoVE·Jean K MilletGary R Whittaker
Apr 30, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kam-Leung SiuDong-Yan Jin
Feb 23, 2020·The Lancet. Respiratory Medicine·Zhe XuFu-Sheng Wang
Feb 23, 2020·The Lancet Infectious Diseases·Ensheng DongLauren Gardner

❮ Previous
Next ❯

Citations

Feb 25, 2021·Nature Biotechnology·Ruili HuangWei Zheng
Apr 22, 2021·Advances and Applications in Bioinformatics and Chemistry : AABC·Bruno O VilloutreixPhilippe Beaune
Jul 13, 2021·Acta Pharmaceutica Sinica. B·Rong XiangShibo Jiang
Aug 28, 2021·Cells·Ankit Shroff, Taras Y Nazarko
Sep 14, 2021·Journal of Chemical Information and Modeling·Thomas R Lane, Sean Ekins

❮ Previous
Next ❯

Methods Mentioned

BETA
Assay
fluorescence microscopy
Infection

Key Resources (RRID) Mentioned

CVCL_0574
CVCL_0030
CVCL_0063
AB_2535811
AB_2137707
AB_2687580
AB_9091
AB_2687579
AB_1904103
AB_2096814

Software Mentioned

EpiAirway
OpenData
Biorender
ImageJ
Columbus Analyzer
Graphpad Prism
Fiji
Excel

Related Concepts

Related Feeds

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Related Papers

BioRxiv : the Preprint Server for Biology
Kirill GorshkovW. Zheng
BioRxiv : the Preprint Server for Biology
Kirill GorshkovWei Zheng
Journal of Korean Medical Science
Wan Beom ParkMyoung Don Oh
© 2021 Meta ULC. All rights reserved