3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Rathnayake, Athri D.; Zheng, Jian; Kim, Yun-Jeong; Perera, Krishani Dinali; Mackin, Samantha; Meyerholz, David K.; Kashipathy, M.M.; Battaile, Kevin P.; Lovell, Scott; Perlman, Stanley; Groutas, William C.; Chang, Kyeong‐Ok

doi:10.1126/scitranslmed.abc5332

Cited by 221 publications

(301 citation statements)

References 56 publications

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“…They showed good performance in in vitro anti-SARS-CoV-2 study and could rapidly enter further clinical trials. Other agents were ab initio designed drugs based on 3 dimensional structure of M pro (Dai et al, 2020;Rathnayake et al, 2020;Zhang et al, 2020b), and these compounds demonstrated the advantage of more potent inhibition and specificity toward M pro .…”

Section: Resultsmentioning

confidence: 99%

Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

Cui

Yang

2020

Front. Mol. Biosci.

100

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The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) rapidly turned into an unprecedented pandemic of coronavirus disease 2019 (COVID-19). This global healthcare emergency marked the third occurrence of a deadly coronavirus (CoV) into the human society after entering the new millennium, which overwhelmed the worldwide healthcare system and affected the global economy. However, therapeutic options for COVID-19 are still very limited. Developing drugs targeting vital proteins in viral life cycle is a feasible approach to overcome this dilemma. Main protease (Mpro) plays a dominant role in processing CoV-encoded polyproteins which mediate the assembly of replication-transcription machinery and is thus recognized as an ideal antiviral target. Here we summarize the recent progress in the discovery of anti-SARS-CoV-2 agents against Mpro. Combining structural study, virtual screen, and experimental screen, numerous therapeutic candidates including repurposed drugs and ab initio designed compounds have been proposed. Such collaborative effort from the scientific community would accelerate the pace of developing efficacious treatment for COVID-19.

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Section: Resultsmentioning

confidence: 99%

Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

Cui

Yang

2020

Front. Mol. Biosci.

100

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“…2b and 2d). Previous structure-activity relationship studies of GC376 indicate that P4 substitution is important, while P3 substitution does not contribute significantly to the binding affinity, as it is solvent exposed 3,8,9,15 . Similarly, the overlaying structures of SARS-CoV M pro + ML188 (R) (PDB: 3V3M) and SARS-CoV-2 M pro + UAWJ247 (PDB: 6XBH) suggested that the 4-tert-butyl at the P2 substitution of ML188 (R) can be replaced by phenyl to occupy the extra space in the S2 pocket ( Figs.…”

Section: Rational Design Of Non-covalent Sars-cov-2 M Pro Inhibitorsmentioning

confidence: 96%

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

Kitamura

Sacco

et al. 2020

Preprint

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The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II and XII, each containing a reactive warhead that covalently modifies the catalytic Cys145. In this study, we report an expedited drug discovery approach by coupling structure-based design and Ugi four-component (Ugi-4CR) reaction methodology to the design of non-covalent Mpro inhibitors. The most potent compound 23R had cellular antiviral activity similar to covalent inhibitors such as GC376. Our designs were guided by overlaying the structure of SARS-CoV Mpro + ML188 (R), a non-covalent inhibitor derived from Ug-4CR, with the X-ray crystal structures of SARS-CoV-2 Mpro + calpain inhibitor XII/GC376/UAWJ247. Binding site analysis suggests a strategy of extending the P2 and P3 substitutions in ML188 (R) to achieve optimal shape complementary with SARS-CoV-2 Mpro. Lead optimization led to the discovery of 23R, which inhibits SARS-CoV-2 Mpro and SARS-CoV-2 viral replication with an IC50 of 0.31 μM and EC50 of 1.27 μM, respectively. The binding and specificity of 23R to SARS-CoV-2 Mpro were confirmed in a thermal shift assay and native mass spectrometry assay. The co-crystal structure of SARS-CoV-2 Mpro with 23R revealed the P2 biphenyl fits snuggly into the S2 pocket and the benzyl group in the α-methylbenzyl faces towards the core of the enzyme, occupying a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study revealed the most potent non-covalent SARS-CoV-2 Mpro inhibitors reported to date and a novel binding pocket that can be explored for Mpro inhibitor design.

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“…Given that SARS-CoV-2 does not encode any neuraminidase protein, neuraminidase inhibitors such as oseltamivir, zanamivir or lamivir are not thought to be effective for treating patients with COVID-19 . However, some studies have found that drugs including arbidol (Zhu et al, 2020), fusion peptide (EK1) (Xia et al, 2019), ganciclovir (Lai et al, 2020), Abelson (Abl) kinase inhibitor (imatinib) (Bernal-Bello et al, 2020), metronidazole (Gharebaghi et al, 2020), antiprotozoal drugs (nitazoxanide and ivermectin) (Mahmoud et al, 2020;Peña-Silva et al, 2020), and 3CL(Pro) inhibitors (Rathnayake et al, 2020) are efficacious when used to prevent SARS-CoV-2 infections in vitro. However, their safety and efficacy in preventing COVID-19 in humans remains to be determined.…”

Section: Other Drugsmentioning

confidence: 99%

COVID-19: the epidemiology and treatment

Ren

2020

Br J Hosp Med

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After initially emerging in late 2019, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly to cause a global pandemic. SARS-CoV-2 is a betacoronavirus that is closely related to severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, all of which can cause severe lung injury, respiratory distress and cytokine storm. While mortality rates associated with SARS-CoV-2 are lower than those associated with severe acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus, it is more contagious and spreads more rapidly than these other viruses. This article summarises the epidemiology and potential options for treating COVID-19 to give a foundation for future studies of the diagnosis, treatment and prevention of this deadly disease.

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3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Cited by 221 publications

References 56 publications

Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

COVID-19: the epidemiology and treatment

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