Development of de-novo coronavirus 3-chymotrypsin-like protease (3CLpro) inhibitors since COVID-19 outbreak: A strategy to tackle challenges of persistent virus infection

Tian, Lei; Qiang, Taotao; Yang, Xiuding; Gao, Yue; Zhai, Xiaopei; Kang, Kairui; Du, Cong; Lu, Qi; Gao, Hong; Zhang, Dezhu; Xie, Xiaolin; Liang, Chengyuan

doi:10.1016/j.ejmech.2023.115979

Cited by 4 publications

(2 citation statements)

References 168 publications

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“…Lufotrelvir was investigated in pre-clinical and clinical trials against COVID-19 but was less successful than nirmatrelvir due to its low oral bioavailability and fast systemic clearance [20]. Additional 3CLpro inhibitors such as simotrelvir, bofutrelvir and 11d, have shown promising e cacy and tolerability in vitro and in vivo [21], [22], [23], [24]. While still not widely available, U.S. Food and Drug Administration (FDA) has granted the Fast Track designation for an investigational COVID-19 oral antiviral ensitrelvir following its approval in Japan and Singapore [25].Since experiments with infectious SARS-CoV-2, SARS-CoV-1, and MERS require biosafety level 3 facilities, virus-free drug screening platforms are strongly desired to foster drug discovery.…”

Section: Introductionmentioning

confidence: 99%

A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro inhibitors

Vlachou,

Nchioua,

Regensburger

et al. 2024

Preprint

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Human coronaviruses (hCoVs) infect millions of people every year. Among these, MERS, SARS-CoV-1, and SARS-CoV-2 caused significant morbidity and mortality and their emergence highlights the risks associated with possible future coronavirus outbreaks. Therefore, broadly-active anti-coronavirus drugs are needed. Pharmacological inhibition of the hCoV protease 3CLpro (Nsp5) in COVID-19 patients is clinically beneficial as shown by the wide and effective use of Paxlovid (nirmaltrevir, ritonavir). However, further treatment options are required due to the emergence of drug resistance in some SARS-CoV-2 strains. To facilitate protease inhibitor discovery and evaluation, we developed an assay allowing rapid and reliable quantification of 3CLpro activity under biosafety level 1 conditions. It is based on an ACE2 receptor - Gal4 transcription factor fusion protein separated by a 3CLpro recognition site. Cleavage by 3CLpro releases the Gal4 transcription factor, which then induces the expression of Gaussia luciferase. Our assay is compatible with 3CLpro proteases from all hCoVs, and allows simultaneous measurement of inhibitory and cytotoxic effects of the tested compounds. Proof-of-concept IC50 measurements confirmed that nirmaltrevir, GC376 and lopinavir inhibit SARS-CoV-2 3CLpro function without inducing cytotoxicity. Overall, the Gaussia luciferase-based reporter assay is suitable for evaluating viral protease function and screening of potential 3CLpro inhibitors.

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Section: Introductionmentioning

confidence: 99%

A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro inhibitors

Vlachou,

Nchioua,

Regensburger

et al. 2024

Preprint

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“…Considering the wide existence of chiral cis -hydrobenzofuran and cis -hydroindole skeletons in biologically active natural products and our efforts in antivirals, we first evaluated the inhibitory activity of cyclization products 2 against SARS-CoV-2 3CL pro , which is a key target for the development of broad-spectrum anti -coronaviral drugs. To our delight, compound 2q showed a promising activity against SARS-CoV-2 3CL pro (Figure , IC 50 = 5.42 ± 0.19 μM) .…”

mentioning

confidence: 99%

Enantioselective Reductive Cyclization of Alkynyl-Tethered Cyclohexadienones Catalyzed by Rhodium Complexes

Wang,

Yang

et al. 2024

Org. Lett.

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Although various types of asymmetric cyclization reactions of 1,6-enynes have been established, simple asymmetric reductive cyclization remains underdeveloped. In this study, the enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones (1,6-enynes) has been developed via a chiral pincer rhodium catalyst, affording cis-hydrobenzofurans and cis-hydroindoles with high enantioselectivities (90−99% ee). Furthermore, several synthetic applications and preliminary inhibitory activity studies against SARS-CoV-2 3CL pro are presented.

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How many organic small molecules might be used to treat COVID-19? From natural products to synthetic agents

Liu

2024

European Journal of Medicinal Chemistry

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Development of de-novo coronavirus 3-chymotrypsin-like protease (3CLpro) inhibitors since COVID-19 outbreak: A strategy to tackle challenges of persistent virus infection

Cited by 4 publications

References 168 publications

A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro inhibitors

A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro inhibitors

Enantioselective Reductive Cyclization of Alkynyl-Tethered Cyclohexadienones Catalyzed by Rhodium Complexes

How many organic small molecules might be used to treat COVID-19? From natural products to synthetic agents

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