About: Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

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About: Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2 Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
Creator	Wu, Yan Sun, Yuan Wang, Rui Shang, Weijuan Xiao, Gengfu Liu, Yingle Xu, Ke Wang, Yong Zou, Gang Zhu, Lili Lan, Ke Li, Honglin Xiong, Rui Zhang, Leike Yu, Chen Ding, Minyi Jiang, Xiaming Lavillete, Dimitri Li, Shiliang Shan, Jiwei Shen, Zihao Tong, Yi Xu, Liuxin Zhao, Yongliang Zhao, Zhenjiang
source	BioRxiv
abstract	Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.
has issue date	2020-03-12(xsd:dateTime)
bibo:doi	10.1101/2020.03.11.983056
has license	biorxiv
sha1sum (hex)	4b566a9544642207c9d03dc6f79507641d1fed0c
schema:url	https://doi.org/10.1101/2020.03.11.983056
resource representing a document's title	Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
schema:publication	bioRxiv
resource representing a document's body	covid:4b566a9544642207c9d03dc6f79507641d1fed0c#body_text
is schema:about of	named entity 'pyrimidine biosynthesis' named entity 'viruses' covid:arg/4b566a9544642207c9d03dc6f79507641d1fed0c named entity 'gene' named entity 'mice' named entity 'chemokine' named entity 'virus replication' named entity 'salvage pathways' named entity 'virus' named entity 'drug-resistant' named entity 'Teriflunomide' named entity 'symptom' named entity 'mice' named entity 'cell growth' named entity 'drug target' named entity 'IL6' named entity 'cell culture' named entity 'dehydrogenation' named entity 'HEPES' named entity 'virus' named entity 'RNA viruses' named entity 'inflammatory diseases' named entity 'cytotoxicity' named entity 'gene' named entity 'antiviral agents' named entity 'pyrimidine de novo synthesis' named entity 'replicon' named entity 'genome' named entity 'SARS-CoV-2' named entity 'pharmacokinetic' named entity 'BALF' named entity 'incubation' named entity 'DHODH' named entity 'virus' named entity 'viral genome replication' named entity 'DHODH' named entity 'X-ray crystal structure' named entity 'DHODH' named entity 'FDA' named entity 'DHODH' named entity 'pro-drug' named entity 'virus' named entity 'GM-CSF' named entity 'nucleotide' named entity 'paraformaldehyde' named entity 'cytokine storm' named entity 'efficacies' named entity 'drug targets' named entity 'pyrimidine' named entity 'chemokines' named entity 'intravenous immunoglobulin' named entity 'therapeutic effects' named entity 'bat' named entity 'infectious diseases' named entity 'positive control' named entity 'H1N1' named entity 'infection' named entity 'viral disease' named entity 'DHODH' named entity 'infection'

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