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Discovery of a Novel Compound with Anti-Venezuelan Equine Encephalitis Virus Activity That Targets the Nonstructural Protein 2
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نویسنده
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chung d.-h. ,jonsson c.b. ,tower n.a. ,chu y.-k. ,sahin e. ,golden j.e. ,noah j.w. ,schroeder c.e. ,sotsky j.b. ,sosa m.i. ,cramer d.e. ,mckellip s.n. ,rasmussen l. ,white e.l. ,schmaljohn c.s. ,julander j.g. ,smith j.m. ,filone c.m. ,connor j.h. ,sakurai y. ,davey r.a.
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منبع
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plos pathogens - 2014 - دوره : 10 - شماره : 6
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چکیده
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Alphaviruses present serious health threats as emerging and re-emerging viruses. venezuelan equine encephalitis virus (veev),a new world alphavirus,can cause encephalitis in humans and horses,but there are no therapeutics for treatment. to date,compounds reported as anti-veev or anti-alphavirus inhibitors have shown moderate activity. to discover new classes of anti-veev inhibitors with novel viral targets,we used a high-throughput screen based on the measurement of cell protection from live veev tc-83-induced cytopathic effect to screen a 340,000 compound library. of those,we identified five novel anti-veev compounds and chose a quinazolinone compound,cid15997213 (ic50 = 0.84 μm),for further characterization. the antiviral effect of cid15997213 was alphavirus-specific,inhibiting veev and western equine encephalitis virus,but not eastern equine encephalitis virus. in vitro assays confirmed inhibition of viral rna,protein,and progeny synthesis. no antiviral activity was detected against a select group of rna viruses. we found mutations conferring the resistance to the compound in the n-terminal domain of nsp2 and confirmed the target residues using a reverse genetic approach. time of addition studies showed that the compound inhibits the middle stage of replication when viral genome replication is most active. in mice,the compound showed complete protection from lethal veev disease at 50 mg/kg/day. collectively,these results reveal a potent anti-veev compound that uniquely targets the viral nsp2 n-terminal domain. while the function of nsp2 has yet to be characterized,our studies suggest that the protein might play a critical role in viral replication,and further,may represent an innovative opportunity to develop therapeutic interventions for alphavirus infection.
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آدرس
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departments of microbiology and immunology,university of louisville,louisville,ky,united states,center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky, United States, departments of microbiology and immunology,university of louisville,louisville,ky,united states,center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky,united states,department of pharmacology and toxicology,university of louisville,louisville,ky, United States, drug discovery department,southern research institute,birmingham,al, United States, center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky, United States, departments of microbiology and immunology,university of louisville,louisville,ky,united states,center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky, United States, university of kansas specialized chemistry center,lawrence,ks, United States, drug discovery department,southern research institute,birmingham,al, United States, university of kansas specialized chemistry center,lawrence,ks, United States, center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky, United States, drug discovery department,southern research institute,birmingham,al, United States, center for predictive medicine for biodefense and emerging infectious diseases,university of louisville,louisville,ky, United States, drug discovery department,southern research institute,birmingham,al, United States, drug discovery department,southern research institute,birmingham,al, United States, drug discovery department,southern research institute,birmingham,al, United States, the united states army medical research institute for infectious diseases,ft. detrick,md, United States, institute for antiviral research,utah state university,logan,ut, United States, the united states army medical research institute for infectious diseases,ft. detrick,md, United States, boston university,boston,ma, United States, boston university,boston,ma, United States, texas biomedical research institute,san antonio,tx, United States, texas biomedical research institute,san antonio,tx, United States
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Authors
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