2,6-Bis-arylmethyloxy-5-hydroxychromones with antiviral activity against both hepatitis C virus (HCV) and SARS-associated coronavirus (SCV)

Kim, Mi Kyoung; Yu, Mi-Sun; Park, Hyeri; Kim, Kyung Bo; Lee, Chaewoon; Cho, Suh Young; Kang, Jihoon; Yoon, Hyunjun; Kim, Dong-Eun; Choo, Hyunah; Jeong, Young-Keun; Chong, Youhoon

doi:10.1016/j.ejmech.2011.09.005

Cited by 57 publications

(46 citation statements)

References 15 publications

(8 reference statements)

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“…Based on their mechanisms of action, CoV helicase inhibitors can be broadly categorized into two groups. The first group includes bananins and 5-hydroxychromone derivatives, which inhibit the unwinding and ATPase activity of SARS-CoV helicase, resulting in inhibition of viral replication in vitro 153,154 . However, the toxicity resulting from the inhibition of cellular ATPases or kinases by these compounds has limited their development for human use.…”

Section: Protein Cage Nanoparticlesmentioning

confidence: 99%

Coronaviruses — drug discovery and therapeutic options

Zumla

Chan

Azhar

et al. 2016

Nat Rev Drug Discov

1,595

1,721

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In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.

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Section: Protein Cage Nanoparticlesmentioning

confidence: 99%

Coronaviruses — drug discovery and therapeutic options

Zumla

Chan

Azhar

et al. 2016

Nat Rev Drug Discov

1,595

1,721

View full text Add to dashboard Cite

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“…Other studies have previously identified potential inhibitors of nsp13. Some of these inhibitors interfere with the unwinding and ATPase activities of nsp13 (23,31,62). Such inhibitors may also interfere with the ATPase activity of cellular ATPase or kinases and affect cellular activities.…”

mentioning

confidence: 99%

Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase

Adedeji

Singh

Calcaterra

et al. 2012

Antimicrob Agents Chemother

115

129

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Severe acute respiratory syndrome (SARS) is a highly contagious disease, caused by SARS coronavirus (SARS-CoV), for which there are no approved treatments. We report the discovery of a potent inhibitor of SARS-CoV that blocks replication by inhibiting the unwinding activity of the SARS-CoV helicase (nsp13). We used a Förster resonance energy transfer (FRET)-based helicase assay to screen the Maybridge Hitfinder chemical library. We identified and validated a compound (SSYA10-001) that specifically blocks the double-stranded RNA (dsRNA) and dsDNA unwinding activities of nsp13, with 50% inhibitory concentrations (IC 50 s) of 5.70 and 5.30 M, respectively. This compound also has inhibitory activity (50% effective concentration [EC 50 ] ‫؍‬ 8.95 M) in a SARS-CoV replicon assay, with low cytotoxicity (50% cytotoxic concentration [CC 50 ] ‫؍‬ >250 M), suggesting that the helicase plays a still unidentified critical role in the SARS-CoV life cycle. Enzyme kinetic studies on the mechanism of nsp13 inhibition revealed that SSYA10-001 acts as a noncompetitive inhibitor of nsp13 with respect to nucleic acid and ATP substrates. Moreover, SSYA10-001 does not affect ATP hydrolysis or nsp13 binding to the nucleic acid substrate. SSYA10-001 did not inhibit hepatitis C virus (HCV) helicase, other bacterial and viral RNA-dependent RNA polymerases, or reverse transcriptase. These results suggest that SSYA10-001 specifically blocks nsp13 through a novel mechanism and is less likely to interfere with the functions of cellular enzymes that process nucleic acids or ATP. Hence, it is possible that SSYA10-001 inhibits unwinding by nsp13 by affecting conformational changes during the course of the reaction or translocation on the nucleic acid. SSYA10-001 will be a valuable tool for studying the specific role of nsp13 in the SARS-CoV life cycle, which could be a model for other nidoviruses and also a candidate for further development as a SARS antiviral target. Severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for the life-threatening viral respiratory illness known as SARS, which emerged from Southern China in November 2002 and spread to other parts of the world, including North America, South America, and Europe (50, 64). There is currently no approved therapeutic agent for the treatment of SARS-CoV infections. Although SARS currently does not pose a public health threat, the likelihood of future occurrences of both SARS-CoV and related viruses necessitates continuous research for identification of antiviral therapies.SARS-CoV contains a single-stranded, 5=-capped, polyadenylated positive-strand RNA genome that is ϳ29.7 kb long (40,45). The first open reading frame (ORF1a/b) encompasses about twothirds of the genome and codes for the replicase proteins (41). Following a Ϫ1 frameshift signal, translation continues in ORF1b after initiation at ORF1a. The virally encoded chymotrypsin-like protease 3CLpro (also called M pro or main protease) and the papain-like protease (PLP) cleave (by autoproteolysis) the newly form...

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“…10A) and the adamantine-derived bananins (Fig. 10B) have a direct effect on the NTPase activity although they are not nucleotide analogs (Kim et al, 2011;Tanner et al, 2005). While chromones were not characterized in detail, bananins seemed to specifically inhibit nucleic acid-stimulated NTPase activity in a non-competitive fashion.…”

Section: Nidovirus Helicases As Drug Targetsmentioning

confidence: 98%

What we know but do not understand about nidovirus helicases

et al. 2015

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Helicases are versatile NTP-dependent motor proteins of monophyletic origin that are found in all kingdoms of life. Their functions range from nucleic acid duplex unwinding to protein displacement and double-strand translocation. This explains their participation in virtually every metabolic process that involves nucleic acids, including DNA replication, recombination and repair, transcription, translation, as well as RNA processing. Helicases are encoded by all plant and animal viruses with a positive-sense RNA genome that is larger than 7 kb, indicating a link to genome size evolution in this virus class. Viral helicases belong to three out of the six currently recognized superfamilies, SF1, SF2, and SF3. Despite being omnipresent, highly conserved and essential, only a few viral helicases, mostly from SF2, have been studied extensively. In general, their specific roles in the viral replication cycle remain poorly understood at present. The SF1 helicase protein of viruses classified in the order Nidovirales is encoded in replicase open reading frame 1b (ORF1b), which is translated to give rise to a large polyprotein following a ribosomal frameshift from the upstream ORF1a. Proteolytic processing of the replicase polyprotein yields a dozen or so mature proteins, one of which includes a helicase. Its hallmark is the presence of an N-terminal multi-nuclear zinc-binding domain, the nidoviral genetic marker and one of the most conserved domains across members of the order. This review summarizes biochemical, structural, and genetic data, including drug development studies, obtained using helicases originating from several mammalian nidoviruses, along with the results of the genomics characterization of a much larger number of (putative) helicases of vertebrate and invertebrate nidoviruses. In the context of our knowledge of related helicases of cellular and viral origin, it discusses the implications of these results for the protein's emerging critical function(s) in nidovirus evolution, genome replication and expression, virion biogenesis, and possibly also post-transcriptional processing of viral RNAs. Using our accumulated knowledge and highlighting gaps in our data, concepts and approaches, it concludes with a perspective on future research aimed at elucidating the role of helicases in the nidovirus replication cycle.

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2,6-Bis-arylmethyloxy-5-hydroxychromones with antiviral activity against both hepatitis C virus (HCV) and SARS-associated coronavirus (SCV)

Cited by 57 publications

References 15 publications

Coronaviruses — drug discovery and therapeutic options

Coronaviruses — drug discovery and therapeutic options

Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase

What we know but do not understand about nidovirus helicases

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