Synthesis, Crystal Structure, Structure−Activity Relationships, and Antiviral Activity of a Potent SARS Coronavirus 3CL Protease Inhibitor

Yang, Syaulan; Chen, Shu Jen; Hsu, Min; Wu, Jen Dar; Tseng, Chien Te K.; Liu, Yu Fan; Chen, Hua Chien; Kuo, Chun Wei; Wu, Changming; Chang, Li‐Chun; Chen, Wen‐Chang; Liao, Shao Ying; Chang, Teng Yuan; Hung, Hsin Hui; Shr, Hui Lin; Liu, Cheng Yuan; Huang, Yu; Chang, Ling-Yin; Hsu, Jen Chi; Peters, C. J.; Wang, Andrew H.J.; Hsu, Ming‐Chen

doi:10.1021/jm0603926

Cited by 150 publications

(175 citation statements)

References 20 publications

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“…Peptide and peptidomimetic aldehyde inhibitors against 3CL pro have been reported (Akaji et al, 2008(Akaji et al, , 2011Zhu et al, 2011) but not tested on live CoVs. However, a potent SARS-CoV 3CL pro peptidomimetic aldehyde inhibitor, TG-0205221, has been shown to block SARS-CoV and human CoV 229E replications (Yang et al, 2006). As shown in this study, we have identified potent and membranepermeable MERS-CoV inhibitors 6b, 6c and 6d using live MERS-CoV virus with EC 50 of 0.6e1.2 mM and S.I.…”

Section: Broad Spectrum Activity Against Human and Feline Covsmentioning

confidence: 62%

“…Though 3C pro and 3CL pro share similar structures at their active sites, subtle differences often discriminate inhibitors. AG7088, an established 3C pro inhibitor, was inactive against SARS-CoV 3CL pro prior to the modifications (Ghosh et al, 2005;Shie et al, 2005;Thanigaimalai et al, 2013;Yang et al, 2006). Unlike AG7088 which contains a, b-unsaturated ester for forming covalent bond with the active-site Cys, our previously reported potent peptidomimetic inhibitors of 3C pro from enterovirus 71 (EV71) contains aldehyde as electrophilic warhead (Kuo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL Pro inhibitors

et al. 2017

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Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory illness with fever, cough and shortness of breath. Up to date, it has resulted in 1826 human infections, including 649 deaths. Analogous to picornavirus 3C protease (3C), 3C-like protease (3CL) is critical for initiation of the MERS-CoV replication cycle and is thus regarded as a validated drug target. As presented here, our peptidomimetic inhibitors of enterovirus 3C (6b, 6c and 6d) inhibited 3CL of MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV) with IC values ranging from 1.7 to 4.7 μM and from 0.2 to 0.7 μM, respectively. In MERS-CoV-infected cells, the inhibitors showed antiviral activity with EC values ranging from 0.6 to 1.4 μM, by downregulating the viral protein production in cells as well as reducing secretion of infectious viral particles into culture supernatants. They also suppressed other α- and β-CoVs from human and feline origin. These compounds exhibited good selectivity index (over 70 against MERS-CoV) and could lead to the development of broad-spectrum antiviral drugs against emerging CoVs and picornaviruses.

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Section: Broad Spectrum Activity Against Human and Feline Covsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL Pro inhibitors

et al. 2017

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“…AG7088 itself was found to be inactive in enzyme assays with SARS-CoV M pro ; however, modifications to the peptidomimetic scaffold lead to significant inhibition potencies. [8,9] The electrophilic building block of these active-site-directed inhibitors consists of an a,b-unsaturated ester function, which undergoes nucleophilic attack by the thiol group of the cysteine residue.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

Paasche¹,

Schiller²,

Schirmeister³

et al. 2010

ChemMedChem

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We investigated the reactions between substituted alpha,beta-unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS-CoV M(pro)) by etacrynic acid derivatives as well as for the excess toxicity of substituted alpha,beta-unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4-addition followed by a ketonization step, and underscores the importance of a base-catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron-pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the s-cis conformation leads to higher reactivity than the s-trans conformation. The computed data explain the trends in measured inhibition potencies of substituted alpha,beta-unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.

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“…A few non-covalent, competitive inhibitors 10 and peptidic, covalent inhibitors have been visualized in SARS 3CL pro crystal structures. 7,8,[11][12][13] The covalent inhibitors studied to date carry either a halomethyl ketone, an epoxide or a 1,4 Michael acceptor function as the reactive "warheads". Such functionalities permanently inactivate the viral peptidase via the formation of a nonhydrolysable covalent linkage to Cys145 as the result of the nucleophilic attack by its S γ atom.…”

Section: Introductionmentioning

confidence: 99%

A Mechanistic View of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-like Peptidase

Jiang

Niu

Cherney

et al. 2007

Journal of Molecular Biology

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The 3C-like main peptidase 3CL pro is a viral polyprotein processing enzyme essential for the viability of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). While it is generalized that 3CL pro and the structurally related 3C pro viral peptidases cleave their substrates via a mechanism similar to that underlying the peptide hydrolysis by chymotrypsin-like serine proteinases (CLSPs), some of the hypothesized key intermediates have not been structurally characterized. Here, we present three crystal structures of SARS 3CL pro in complex with each of two members of a new class of peptide-based phthalhydrazide inhibitors. Both inhibitors form an unusual thiiranium ring with the nucleophilic sulfur atom of Cys145, trapping the enzyme's catalytic residues in configurations similar to the intermediate states proposed to exist during the hydrolysis of native substrates. Most significantly, our crystallographic data are consistent with a scenario in which a water molecule, possibly via indirect coordination from the carbonyl oxygen of Thr26, has initiated nucleophilic attack on the enzyme-bound inhibitor. Our data suggest that this structure resembles that of the proposed tetrahedral intermediate during the deacylation step of normal peptidyl cleavage.

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Synthesis, Crystal Structure, Structure−Activity Relationships, and Antiviral Activity of a Potent SARS Coronavirus 3CL Protease Inhibitor

Cited by 150 publications

References 20 publications

Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL Pro inhibitors

Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL Pro inhibitors

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

A Mechanistic View of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-like Peptidase

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