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1.
EMBO J ; : e111608, 2022 Jul 14.
Article in English | MEDLINE | ID: covidwho-1934722

ABSTRACT

The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.

2.
FEBS Open Bio ; 12(1): 285-294, 2022 01.
Article in English | MEDLINE | ID: covidwho-1540045

ABSTRACT

Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , COVID-19/prevention & control , Plant Preparations/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Benzylisoquinolines/chemistry , Benzylisoquinolines/metabolism , COVID-19/virology , Chlorocebus aethiops , Coronavirus M Proteins/antagonists & inhibitors , Coronavirus M Proteins/chemistry , Coronavirus M Proteins/metabolism , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Preparations/chemistry , Plant Preparations/metabolism , Protein Binding , Protein Conformation , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Stephania/chemistry , Vero Cells
3.
iScience ; 24(4): 102367, 2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1157438

ABSTRACT

Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling in vitro antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.

5.
Proceedings for Annual Meeting of The Japanese Pharmacological Society ; 93(0):2-ES-3, 2020.
Article | WHO COVID | ID: covidwho-9050

ABSTRACT

Abstract In silico prediction based on the protein structures of SARS-CoV2 is effective to find the putative drug candidates from the approved drugs, as drug repositioning. The main protease, 3CL protease, of SARS-Cov2 is essential for proteolytic maturation of the virus, and inhibiting its function could prevent the COVID-19 spreading. Here, recent activities in the in-silico unit of AMED-BINDS are introduced. Hirokawa et al. adopted an in silico docking-based screening approach, which combines molecular docking with a protein-ligand interaction fingerprint (PLIF) scoring method, utilizing the crystal structure of SARS-Cov2 3CL protease (PDB: 6LU7) and a database of known drugs (KEGG-Drug). Selected drugs have the binding modes similar to PLIF of the known active N3 inhibitors with favorable docking scores. They identified one hundred and several dozen potentially candidate drugs for 3CL protease inhibitors, which are already approved as antiviral, HIV protease inhibitors, antibacterial or antineoplastic agents. Sekijima et al. analyzed the interactions between 3CL protease and the drug candidate compounds using molecular dynamics simulation. Through this study, they aim to elucidate the interactions between 3CL protease and the drugs. The chemical compound libraries in AMED-BINDS will also be available in the future assay studies.

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