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Oral Nonpeptidic, Noncovalent Triazine Coronavirus Main Protease Inhibitors for Treating COVID-19.

ABSTRACT: The current COVID-19 global pandemic caused by SARS-CoV-2 has claimed more than 6 million lives since its emergence in December 2019. The first oral coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA in December 2021, with a twice-daily dosing regimen in combination with ritonavir. In March 2022, Shionogi & Co. announced their single-agent, once-daily oral SARS-CoV-2 main protease inhibitor, ensitrelvir, was granted approval for global phase 3 clinical trials. Unlike nirmatrelvir, ensitrelvir is a nonpeptidic, noncovalent, small molecule. This Patent Highlight describes key structures and their inhibitory activities in Shionogi & Co.'s and Hokkaido University's patent WO 2022/138987 A1.

SUBMITTER: Chia CSB

PROVIDER: S-EPMC9465980 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Oral Nonpeptidic, Noncovalent Triazine Coronavirus Main Protease Inhibitors for Treating COVID-19.

Chia C S Brian CSB Inoue Masafumi M

ACS medicinal chemistry letters 20220819 9

The current COVID-19 global pandemic caused by SARS-CoV-2 has claimed more than 6 million lives since its emergence in December 2019. The first oral coronavirus main protease inhibitor, nirmatrelvir, was granted Emergency Use Authorization by the U.S. FDA in December 2021, with a twice-daily dosing regimen in combination with ritonavir. In March 2022, Shionogi & Co. announced their single-agent, once-daily oral SARS-CoV-2 main protease inhibitor, ensitrelvir, was granted approval for global phas ...[more]

PMID: 36105344

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Project description:The rapid global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused serious health problems, highlighting the urgent need for antiviral drugs. The viral main protease (Mpro) plays an important role in viral replication and thus remains the target of choice for the prevention or treatment of several viral diseases due to high sequence and structural conservation. Prolonged use of viral protease inhibitors can lead to the development of mutants resistant to those inhibitors and to many of the available antiviral drugs. Here, we used feline infectious peritonitis virus (FIPV) as a model to investigate its development of resistance under pressure from the Mpro inhibitor GC376. Passage of wild-type (WT) FIPV in the presence of GC376 selected for a mutation in the nsp12 region where Mpro cleaves the substrate between nsp12 and nsp13. This mutation confers up to 3-fold resistance to GC376 and nirmatrelvir, as determined by EC50 assay. In vitro biochemical and cellular experiments confirmed that FIPV adapts to the stress of GC376 by mutating the nsp12 and nsp13 hydrolysis site to facilitate cleavage by Mpro and release to mediate replication and transcription. Finally, we demonstrate that GC376 cannot treat FIP-resistant mutants that cause FIP in animals. Taken together, these results suggest that Mpro affects the replication of coronaviruses (CoVs) and the drug resistance to GC376 by regulating the amount of RdRp from a distant site. These findings provide further support for the use of an antiviral drug combination as a broad-spectrum therapy to protect against contemporary and emerging CoVs. IMPORTANCE CoVs cause serious human infections, and antiviral drugs are currently approved to treat these infections. The development of protease-targeting therapeutics for CoV infection is hindered by resistance mutations. Therefore, we should pay attention to its resistance to antiviral drugs. Here, we identified possible mutations that lead to relapse after clinical treatment of FIP. One amino acid substitution in the nsp12 polymerase at the Mpro cleavage site provided low-level resistance to GC376 after selection exposure to the GC376 parental nucleoside. Resistance mutations enhanced FIPV viral fitness in vitro and attenuated the therapeutic effect of GC376 in an animal model of FIPV infection. Our research explains the evolutionary characteristics of coronaviruses under antiviral drugs, which is helpful for a more comprehensive understanding of the molecular basis of virus resistance and provides important basic data for the effective prevention and control of CoVs.

Project description:SARS coronavirus main protease (SARS-CoV M(pro)) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV M(pro). Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV M(pro) requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV M(pro) in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV M(pro), with K(i) values in the ?M range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV M(pro) in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV M(pro), with K(i)=2.24±0.58 ?M. These results show that the stringent substrate specificity of the SARS-CoV M(pro) with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.

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Oral Nonpeptidic, Noncovalent Triazine Coronavirus Main Protease Inhibitors for Treating COVID-19.

Publications

Oral Nonpeptidic, Noncovalent Triazine Coronavirus Main Protease Inhibitors for Treating COVID-19.

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