Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors

The severe acute respiratory syndrome-causing coronavirus 2 (SARS-CoV-2) papain-like protease (PL ) and main protease (M ) play an important role in viral replication events and are important targets for anti-coronavirus drug discovery. In search of these protease inhibitors, we screened a library o...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-08, Vol.24 (17), p.13491
Main Authors: Bagdonas, Martynas, Čerepenkaitė, Kamilė, Mickevičiūtė, Aurelija, Kananavičiūtė, Rūta, Grybaitė, Birutė, Anusevičius, Kazimieras, Rukšėnaitė, Audronė, Kojis, Tautvydas, Gedgaudas, Marius, Mickevičius, Vytautas, Matulis, Daumantas, Zubrienė, Asta, Matulienė, Jurgita
Format: Article
Language:English
Subjects:
Amino acids
Chemical bonds
Coronaviruses
COVID-19
COVID-19 vaccines
disulfide
Disulfides
Drug dosages
Enzymes
Epidemics
Health aspects
Humans
Infections
Laboratories
Libraries
main protease
Mass spectrometry
Papain
papain-like protease
Protease inhibitors
Protease Inhibitors - pharmacology
Proteases
Proteins
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
thermal shift assay
thiazole
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Summary:The severe acute respiratory syndrome-causing coronavirus 2 (SARS-CoV-2) papain-like protease (PL ) and main protease (M ) play an important role in viral replication events and are important targets for anti-coronavirus drug discovery. In search of these protease inhibitors, we screened a library of 1300 compounds using a fluorescence thermal shift assay (FTSA) and identified 53 hits that thermally stabilized or destabilized PL . The hit compounds structurally belonged to two classes of small molecules: thiazole derivatives and symmetrical disulfide compounds. Compound dissociation constants (K ) were determined using an enzymatic inhibition method. Seven aromatic disulfide compounds were identified as efficient PL inhibitors with K values in the micromolar range. Two disulfides displayed six-fold higher potency for PL (K = 0.5 µM) than for M . The disulfide derivatives bound covalently to both proteases, as confirmed through mass spectrometry. The identified compounds can serve as lead compounds for further chemical optimization toward anti-COVID-19 drugs.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241713491