Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses

Adedeji, Adeyemi O.; Singh, Kamalendra; Kassim, Ademola; Coleman, Christopher M.; Elliott, Ruth; Weiss, Susan R.; Frieman, Matthew B.; Sarafianos, Stefan G.

doi:10.1128/aac.02994-14

Cited by 107 publications

(112 citation statements)

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“…Type I IFN and ribavirin have been reported to ameliorate disease in infected macaques (15), and small molecules targeting diverse intracellular pathways have been shown to inhibit MERS-CoV in vitro (16)(17)(18). Furthermore, experimental immunogens can elicit an anti-MERS-CoV response (19,20).…”

mentioning

confidence: 97%

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

Pascal

Coleman

Mujica

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and κ light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics.

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mentioning

confidence: 97%

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

Pascal

Coleman

Mujica

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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201

255

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“…These include naturally occurring flavonoids (Yu et al, 2012), chromones (Kim et al, 2011), and bananins (Kesel, 2005;Tanner et al, 2005), all exhibiting in vitro IC 50 values in the low-micromolar range. Other compounds appear to target the helicase of nsp13 activity more specifically, like the triazole SSYA10-001, which was found to inhibit the replication of multiple beta-CoVs (SARS-CoV, MERS-CoV, and MHV) in cell culture-based infection models (Adedeji et al, 2012b(Adedeji et al, , 2014. The IC 50 value in in vitro helicase assays was about 5.5 μM, whereas EC 50 values in cell cultures assays were in the range of 7-25 μM, depending on the CoV analyzed, suggesting that broad-spectrum activity may indeed be achieved.…”

Section: The Coronavirus Helicase As Drug Targetmentioning

confidence: 99%

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

Snijder

Decroly

Ziebuhr

2016

Advances in Virus Research

536

620

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Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26-32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. The primary functions that direct coronavirus RNA synthesis and processing reside in nonstructural protein (nsp) 7 to nsp16, which are cleavage products of two large replicase polyproteins translated from the coronavirus genome. Significant progress has now been made regarding their structural and functional characterization, stimulated by technical advances like improved methods for bioinformatics and structural biology, in vitro enzyme characterization, and site-directed mutagenesis of coronavirus genomes. Coronavirus replicase functions include more or less universal activities of plus-stranded RNA viruses, like an RNA polymerase (nsp12) and helicase (nsp13), but also a number of rare or even unique domains involved in mRNA capping (nsp14, nsp16) and fidelity control (nsp14). Several smaller subunits (nsp7-nsp10) act as crucial cofactors of these enzymes and contribute to the emerging "nsp interactome." Understanding the structure, function, and interactions of the RNA-synthesizing machinery of coronaviruses will be key to rationalizing their evolutionary success and the development of improved control strategies.

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“…In agreement with this hypothesis, bananins exhibited good selectivity with an EC 50 of <10 M and CC 50 of 390 M. Whether this site may also be present in other nidovirus helicases has not been tested so far. Another noncompetitive inhibitor was identified by Adedeji et al (2012bAdedeji et al ( , 2014. In contrast to the above compounds, it neither had an effect on the NTPase or nucleic acid-binding activities nor was it able to bind non-specifically to nucleic acids.…”

Section: Nidovirus Helicases As Drug Targetsmentioning

confidence: 99%

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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Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses

Cited by 107 publications

References 11 publications

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

What we know but do not understand about nidovirus helicases

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