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1.
ACS Infect Dis ; 8(5): 1022-1030, 2022 05 13.
Article in English | MEDLINE | ID: covidwho-1783938

ABSTRACT

The global COVID-19 pandemic underscores the dire need for effective antivirals. Encouraging progress has been made in developing small-molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the development of papain-like protease (PLpro) inhibitors faces several obstacles. Nevertheless, PLpro represents a high-profile drug target given its multifaceted roles in viral replication. PLpro is involved in not only the cleavage of viral polyprotein but also the modulation of host immune response. In this study, we conducted a drug-repurposing screening of PLpro against the MedChemExpress bioactive compound library and identified three hits, EACC, KY-226, and tropifexor, as potent PLpro inhibitors with IC50 values ranging from 3.39 to 8.28 µM. The three hits showed dose-dependent binding to PLpro in the thermal shift assay. In addition, tropifexor inhibited the cellular PLpro activity in the FlipGFP assay with an IC50 of 10.6 µM. Gratifyingly, tropifexor showed antiviral activity against SARS-CoV-2 in Calu-3 cells at noncytotoxic concentrations. Overall, tropifexor represents a novel PLpro inhibitor that can be further developed as SARS-CoV-2 antivirals.


Subject(s)
Benzothiazoles , Coronavirus Papain-Like Proteases , Drug Repositioning , Isoxazoles , SARS-CoV-2 , Antiviral Agents/chemistry , Benzothiazoles/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Humans , Isoxazoles/pharmacology , Pandemics , SARS-CoV-2/drug effects
2.
Cell Rep ; 35(1): 108940, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1157178

ABSTRACT

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , DNA Damage , Isoxazoles/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/physiology , Virus Replication/drug effects , A549 Cells , Animals , COVID-19/metabolism , COVID-19/pathology , Chlorocebus aethiops , Drug Evaluation, Preclinical , HEK293 Cells , HeLa Cells , Humans , MAP Kinase Signaling System/drug effects , Middle East Respiratory Syndrome Coronavirus/metabolism , Vero Cells
3.
Int J Mol Sci ; 21(17)2020 Aug 27.
Article in English | MEDLINE | ID: covidwho-831264

ABSTRACT

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.


Subject(s)
Anti-Bacterial Agents/pharmacology , Membrane Transport Proteins/metabolism , Mycobacterium Infections, Nontuberculous/drug therapy , Nontuberculous Mycobacteria/metabolism , Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/metabolism , Biological Transport/drug effects , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Gene Expression Regulation, Bacterial/drug effects , Humans , Iodophors/pharmacology , Iodophors/therapeutic use , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Mycobacterium Infections, Nontuberculous/metabolism , Mycolic Acids/metabolism , Nontuberculous Mycobacteria/drug effects , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use
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