Structural basis of mercury‐ and zinc‐conjugated complexes as SARS‐CoV 3C‐like protease inhibitors

Lee, Cheng-Chung; Kuo, C.J.; Hsu, Min‐Feng; Liang, Po‐Huang; Fang, Jim‐Min; Shie, Jiun‐Jie; Wang, Andrew H.-J.

doi:10.1016/j.febslet.2007.10.048

Cited by 57 publications

(60 citation statements)

References 26 publications

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“…These include competitive inhibitors phenyl mercuric acetate (168, K i = 0.7 μM), thimerosal (169, K i = 2.4 μM), and phenyl mercuric nitrate (170, K i = 0.3 μM) ( Figure 33). 121,122 However, inhibition was more pronounced using zinc-conjugated compounds (171−174), i.e., 1-hydroxypyridine-2-thione zinc (171, K i = 0.17 μM) compared to Zn 2+ ions alone (K i = 1.1 μM). The X-ray crystal structure of SARS-CoV 3CL pro −168 (PDB ID 1Z1I) revealed that phenyl-bound mercury occupied the S3 pocket, which is responsible for its enzymatic activity.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

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Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CL(pro), has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CL(pro) chemotherapies discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CL(pro). Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

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“…To date, several crystal structures of CoV M pro and the complex of M pro -inhibitor have been determined (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, the 3-dimensional structure of FIPV M pro is still unavailable, deterring rational drug design against FIP.…”

mentioning

confidence: 99%

Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

Wang

Chen

Liu

et al. 2016

J Virol

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Coronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. Feline infectious peritonitis virus (FIPV) belongs to the genus Alphacoronavirus, resulting in a lethal systemic granulomatous disease called feline infectious peritonitis (FIP), which is one of the most important fatal infectious diseases of cats worldwide. No specific vaccines or drugs have been approved to treat FIP. CoV main proteases (M pro s) play a pivotal role in viral transcription and replication, making them an ideal target for drug development. Here, we report the crystal structure of FIPV M pro in complex with dual inhibitors, a zinc ion and a Michael acceptor. The complex structure elaborates a unique mechanism of two distinct inhibitors synergizing to inactivate the protease, providing a structural basis to design novel antivirals and suggesting the potential to take advantage of zinc as an adjunct therapy against CoV-associated diseases. C oronaviruses (CoVs) infect humans and animals, causing various highly prevalent and severe diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (1, 2). Feline infectious peritonitis virus (FIPV) belongs to the genus Alphacoronavirus in the subfamily Coronavirinae. It is a highly virulent mutant of the feline enteric coronavirus (FECV), which is closely related to transmissible gastroenteritis coronavirus (TGEV) of pigs and canine coronavirus (CCV) (3). In contrast with FECV, which causes asymptomatic or mild infection in cats and other felines, FIPV is an etiologic agent resulting in a lethal systemic granulomatous disease called feline infectious peritonitis (FIP), one of the most important fatal infectious diseases of cats worldwide (4). There are no effective drugs specific for FIP. The development of vaccines toward FIPV has also failed due to the antibody-dependent enhancement, where infection of the monocyte/macrophage lineage by FIPV is enhanced in the presence of antibodies (5). Thus, discovery of effective antivirals against FIPV is desired for the treatment of FIP.Similar to other alphacoronaviruses, FIPV contains a single positive-stranded RNA genome that is composed of two overlapping open reading frames (ORFs), ORF1a and ORF1b at the 5= end, encoding two large polyproteins, pp1a and pp1ab (6). These two polyproteins are subsequently cleaved into 16 nonstructural proteins (nsp1 to nsp16), which assemble into a membrane-anchored replication machinery for transcription/replication. Cleavage is regulated by two proteases: the main protease (M pro , also called nsp5 or 3C-like protease), and the papain-like protease (PL pro ). PL pro processes the N-terminal end of pp1a/pp1ab into nsp1, nsp2, and nsp3, while M pro cleaves the polyproteins at 11 sites to release nsp4 to nsp16 (6). The essential roles M pro plays in the viral life cycle and the lack of a cellular homologue in the human genome make it an attractive target for drug design.To date, several crystal structures of CoV M pro and the complex of M pro -inhibitor...

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“…Many excellent and exhaustive studies have based this mechanism of catalysis and the structure of the catalytic site architecture to design several different classes of peptidomimetic inhibitors targeted against M pro of coronaviruses (including SARS) and other pathogenic viruses. Several M pro inhibitors have also been structurally characterized (Akaji et al, 2011;Bacha et al, 2008;Chu et al, 2006;Chuck et al, 2013;Grum-Tokars et al, 2008;Lee et al, 2007;Lee et al, 2009;Lee et al, 2005;Shan and Xu, 2005;Shao et al, 2007;Turlington et al, 2013;Verschueren et al, 2008;Wei et al, 2006;Yang et al, 2006;Yang et al, 2003;Yang et al, 2007;Zhang et al, 2010;Zhu et al, 2011).…”

Section: Functionmentioning

confidence: 99%

Atlas of coronavirus replicase structure

et al. 2014

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The international response to SARS-CoV has produced an outstanding number of protein structures in a very short time. This review summarizes the findings of functional and structural studies including those derived from cryoelectron microscopy, small angle X-ray scattering, NMR spectroscopy, and X-ray crystallography, and incorporates bioinformatics predictions where no structural data is available. Structures that shed light on the function and biological roles of the proteins in viral replication and pathogenesis are highlighted. The high percentage of novel protein folds identified among SARS-CoV proteins is discussed.

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Structural basis of mercury‐ and zinc‐conjugated complexes as SARS‐CoV 3C‐like protease inhibitors

Cited by 57 publications

References 26 publications

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

Atlas of coronavirus replicase structure

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