tetano
Editor, Senior Moderator
Protein Cell
. 2020 Aug 4.
doi: 10.1007/s13238-020-00768-w. Online ahead of print.
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
Rui Xiong[SUP] 1 [/SUP], Leike Zhang[SUP] 2 [/SUP], Shiliang Li[SUP] 1 [/SUP], Yuan Sun[SUP] 2 [/SUP], Minyi Ding[SUP] 1 [/SUP], Yong Wang[SUP] 3 [/SUP], Yongliang Zhao[SUP] 3 [/SUP], Yan Wu[SUP] 2 [/SUP], Weijuan Shang[SUP] 2 [/SUP], Xiaming Jiang[SUP] 2 [/SUP], Jiwei Shan[SUP] 1 [/SUP], Zihao Shen[SUP] 1 [/SUP], Yi Tong[SUP] 1 [/SUP], Liuxin Xu[SUP] 1 [/SUP], Yu Chen[SUP] 3 [/SUP], Yingle Liu[SUP] 3 [/SUP], Gang Zou[SUP] 4 [/SUP], Dimitri Lavillete[SUP] 4 [/SUP], Zhenjiang Zhao[SUP] 1 [/SUP], Rui Wang[SUP] 1 [/SUP], Lili Zhu[SUP] 1 [/SUP], Gengfu Xiao[SUP] 2 [/SUP], Ke Lan[SUP] 3 [/SUP], Honglin Li[SUP] 5 [/SUP], Ke Xu[SUP] 6 7 [/SUP]
Affiliations
Abstract
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC[SUB]50[/SUB] of 17 nmol/L and an SI value of 10,505.88 in infected cells. 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 knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Keywords: DHODH inhibitors; SARS-CoV-2; de novo pyrimidine biosynthesis; immuno-regulation; influenza viruses; virus replication.
. 2020 Aug 4.
doi: 10.1007/s13238-020-00768-w. Online ahead of print.
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
Rui Xiong[SUP] 1 [/SUP], Leike Zhang[SUP] 2 [/SUP], Shiliang Li[SUP] 1 [/SUP], Yuan Sun[SUP] 2 [/SUP], Minyi Ding[SUP] 1 [/SUP], Yong Wang[SUP] 3 [/SUP], Yongliang Zhao[SUP] 3 [/SUP], Yan Wu[SUP] 2 [/SUP], Weijuan Shang[SUP] 2 [/SUP], Xiaming Jiang[SUP] 2 [/SUP], Jiwei Shan[SUP] 1 [/SUP], Zihao Shen[SUP] 1 [/SUP], Yi Tong[SUP] 1 [/SUP], Liuxin Xu[SUP] 1 [/SUP], Yu Chen[SUP] 3 [/SUP], Yingle Liu[SUP] 3 [/SUP], Gang Zou[SUP] 4 [/SUP], Dimitri Lavillete[SUP] 4 [/SUP], Zhenjiang Zhao[SUP] 1 [/SUP], Rui Wang[SUP] 1 [/SUP], Lili Zhu[SUP] 1 [/SUP], Gengfu Xiao[SUP] 2 [/SUP], Ke Lan[SUP] 3 [/SUP], Honglin Li[SUP] 5 [/SUP], Ke Xu[SUP] 6 7 [/SUP]
Affiliations
- PMID: 32754890
- DOI: 10.1007/s13238-020-00768-w
Abstract
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC[SUB]50[/SUB] of 17 nmol/L and an SI value of 10,505.88 in infected cells. 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 knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Keywords: DHODH inhibitors; SARS-CoV-2; de novo pyrimidine biosynthesis; immuno-regulation; influenza viruses; virus replication.