Recent progress in the discovery of inhibitors targeting coronavirus proteases

Wang, Haofeng; Xue, Song; Yang, Haitao; Chen, Cheng

doi:10.1007/s12250-015-3711-3

Cited by 51 publications

(42 citation statements)

References 55 publications

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“…Domain I and domain II form a chymotrypsin-like fold for proteolysis, while domain III mainly participates in the formation of homodimers [12]. In the catalytic site, the catalytic dyad and potential substrate-binding pockets (S1eS5) were discovered [13,14]. On the other hand, the regulation of M pro activity was investigated to gain a deeper understanding of the cleavage mechanism.…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor

Cui

Chen

et al. 2019

Biochemical and Biophysical Research Communications

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a b s t r a c tMouse hepatitis virus A59 (MHV-A59) is a representative member of the genus betacoronavirus within the subfamily Coronavirinae, which infects the liver, brain and respiratory tract. Through different inoculation routes, MHV-A59 can provide animal models for encephalitis, hepatitis and pneumonia to explore viral life machinery and virus-host interactions. In viral replication, non-structural protein 5 (Nsp5), also termed main protease (M pro ), plays a dominant role in processing coronavirus-encoded polyproteins and is thus recognized as an ideal target of anti-coronavirus agents. However, no structure of the MHV-A59 M pro has been reported, and molecular exploration of the catalysis mechanism remains hindered. Here, we solved the crystal structure of the MHV-A59 M pro complexed with a Michael acceptor-based inhibitor, N3. Structural analysis revealed that the Cb of the vinyl group of N3 covalently bound to C145 of the catalytic dyad of M pro , which irreversibly inactivated cysteine protease activity. The lactam ring of the P1 side chain and the isobutyl group of the P2 side chain, which mimic the conserved residues at the same positions of the substrate, fit well into the S1 and S2 pockets. Through a comparative study with M pro of other coronaviruses, we observed that the substrate-recognition pocket and enzyme inhibitory mechanism is highly conservative. Altogether, our study provided structural features of MHV-A59 M pro and indicated that a Michael acceptor inhibitor is an ideal scaffold for antiviral drugs.

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Section: Introductionmentioning

confidence: 99%

The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor

Cui

Chen

et al. 2019

Biochemical and Biophysical Research Communications

Self Cite

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“…Infections with human coronaviruses (HCoVs) 229E (Hamre & Procknow, 1966), OC43 (McIntosh et al, 1967), NL63 (van der Hoek et al, 2004), and HKU1 (Woo et al, 2005) cause relatively mild symptoms in most cases, whereas severe acute res-piratory syndrome coronavirus (SARS-CoV; Ksiazek et al, 2003;Kuiken et al, 2003;Peiris et al, 2003) and Middle-East respiratory syndrome coronavirus (MERS-CoV; Zaki et al, 2012) are connected with severe respiratory-tract infection and, in particular in case of MERS-CoV, acute renal failure (Eckerle et al, 2013), leading to high case-fatality rates of ~10 and 35%, respectively. In spite of 13 years of research on SARS-CoV (Hilgenfeld & Peiris, 2013), no approved drugs or vaccines are available for the treatment or prevention of coronavirus infection (Wang et al, 2016). This is mainly due to the fact that although these emerging viruses have devastating effects on those infected, the absolute numbers of cases (~8000 for SARS, 1733 so far for MERS; (http://www.who.int)) imply that the de-velopment of specific antivirals is very likely not commercially viable.…”

Section: Introductionmentioning

confidence: 99%

Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin

Lei

Hilgenfeld

2016

Virol. Sin.

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The papain-like protease (PL(pro)) of Middle-East respiratory syndrome coronavirus (MERS-CoV) has proteolytic, deubiquitinating, and deISGylating activities. The latter two are involved in the suppression of the antiviral innate immune response of the host cell. To contribute to an understanding of this process, we present here the X-ray crystal structure of a complex between MERS-CoV PL(pro) and human ubiquitin (Ub) that is devoid of any covalent linkage between the two proteins. Five regions of the PL(pro) bind to two areas of the Ub. The C-terminal five residues of Ub, RLRGG, are similar to the P5-P1 residues of the polyprotein substrates of the PL(pro) and are responsible for the major part of the interaction between the two macromolecules. Through sitedirected mutagenesis, we demonstrate that conserved Asp165 and non-conserved Asp164 are important for the catalytic activities of MERS-CoV PL(pro). The enzyme appears not to be optimized for catalytic efficiency; thus, replacement of Phe269 by Tyr leads to increased peptidolytic and deubiquitinating activities. Ubiquitin binding by MERS-CoV PL(pro) involves remarkable differences compared to the corresponding complex with SARS-CoV PL(pro). The structure and the mutational study help understand common and unique features of the deubiquitinating activity of MERS-CoV PL(pro).

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“…SSYA10-001, the helicase nsp13 inhibitor, blocks the replication of SARS-CoV and MERS-CoV [40]. Some coronavirus protease inhibitors, such as the compound 5c, can also suppress viral replication [41,42]. The fifth group of inhibitors includes those with undefined mechanism of action.…”

Section: Small-molecule Viral Inhibitors Against Sars-cov and Mers-covmentioning

confidence: 99%

Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses

Wang

Zou

et al. 2017

Front. Med.

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In recent years, unexpected outbreaks of infectious diseases caused by emerging and re-emerging viruses have become more frequent, which is possibly due to environmental changes. These outbreaks result in the loss of life and economic hardship. Vaccines and therapeutics should be developed for the prevention and treatment of infectious diseases. In this review, we summarize and discuss the latest progress in the development of small-molecule viral inhibitors against highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, Ebola virus, and Zika virus. These viruses can interfere with the specific steps of viral life cycle by blocking the binding between virus and host cells, disrupting viral endocytosis, disturbing membrane fusion, and interrupting viral RNA replication and translation, thereby demonstrating potent therapeutic effect against various emerging and re-emerging viruses. We also discuss some general strategies for developing small-molecule viral inhibitors.

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Recent progress in the discovery of inhibitors targeting coronavirus proteases

Cited by 51 publications

References 55 publications

The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor

The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor

Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin

Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses

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