1. Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients
- Author
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Tianxiao Liu, Songyuan Luo, Peter Libby, and Guo-Ping Shi
- Subjects
0301 basic medicine ,Camostat mesylate ,viruses ,Cathepsin L ,medicine.disease_cause ,APC, antigen presenting cell ,Protease inhibitor cocktail ,SI, selectivity index ,0302 clinical medicine ,SARS-S, SARS S protein ,Nafamostat mesylate ,CC50, the half cytotoxic concentration ,Pharmacology (medical) ,MERS-CoV, Middle East respiratory syndrome-coronavirus ,Medicine, Chinese Traditional ,Drug Approval ,Coronavirus ,GFP, green fluorescent protein ,education.field_of_study ,Clinical Trials as Topic ,Serine Endopeptidases ,SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2 ,CatS, cathepsin S ,virus diseases ,RBD, receptor-binding domain ,Chloroquine ,Cysteine protease ,Anti-Bacterial Agents ,HIV, human immunodeficiency virus ,S1, S2, spike protein subunits ,CPE, cytopathic effect ,030220 oncology & carcinogenesis ,EC50, the half effective concentration ,Drug Therapy, Combination ,Coronavirus Infections ,medicine.drug ,Population ,Pneumonia, Viral ,Antigen-Presenting Cells ,IC50, the half maximal inhibitory concentration ,Biology ,ACE2, angiotensin-converting enzyme 2 ,Antiviral Agents ,Virus ,Article ,WHO, World Health Organization ,ATII, human lung type-II alveolar epithelial cells ,03 medical and health sciences ,Antimalarials ,Betacoronavirus ,Immune system ,CatL, cathepsin L ,medicine ,Humans ,Immunologic Factors ,education ,Pandemics ,COVID-19, coronavirus disease ,Pharmacology ,Host cell endosome membrane ,Dose-Response Relationship, Drug ,SARS-CoV-2 ,ChiCTR, Chinese Clinical Trial Registry ,United States Food and Drug Administration ,ARDS, adult respiratory distress syndrome ,COVID-19 ,DEP, dual-envelop pseudotype ,Virology ,FDA, Food and Drug Administration ,United States ,MW, molecule weight ,030104 developmental biology ,MRSA, Methicillin-resistant Staphylococcus aureus ,biology.protein ,TMPRSS2, transmembrane serine protease 2 ,Ritonavir ,βCoV, betacoronavirus - Abstract
The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system., Key messages • There are over 2118 on-going clinical trials for COVID-19 patients, but current results are limited. • Host cell membrane CatL and TMPRSS2 promote coronavirus cell entry by removing the virus surface spike protein S1 subunit. • In host cell endosomes, CatL removes the S1 subunit and promotes viral membrane fusion, viral RNA release, and replication. • At least 7 CatL-selective inhibitors effectively block coronavirus infection of human cells. • At least 10 US FDA-approved drugs exert CatL inhibitory activity. • Combined use of TMPRSS2 inhibitor camostat and CatL inhibitors or FDA-approved CatL inhibitory drugs merits consideration for urgent testing in COVID-19 patients. • Chloroquine-induced endosomal pH increase and protease inactivation inhibit coronavirus infection, but impair human adaptive immunity. • The protease inhibitor cocktail therapy proposed here could block coronavirus infection while sparing human adaptive immunity.
- Published
- 2020