Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Xiong, Rui; Zhang, Leike; Li, Shiliang; Sun, Yuan; Ma, Ding; Wang, Yong; Zhao, Yongliang; Wu, Yan; Shang, Weijuan; Jiang, Xiaming; Shan, Jiwei; Shen, Zihao; Tong, Yao; Xu, Liuxin; Chen, Yu; Liu, Yingle; Zou, Gang; Lavillete, Dimitri; Zhao, Zhenjiang; Wang, Rui; Zhu, Lili; Xiao, Gengfu; Lan, Ke; Li, Honglin; Xu, Ke

doi:10.1007/s13238-020-00768-w

Cited by 144 publications

(185 citation statements)

References 60 publications

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“…28 Still, efforts to develop broadly acting antivirals via targeting DHODH continue and a recent study reported the discovery of two promising DHODH inhibitors S312 and S416 ( Figure 1) with low in vivo toxicity starting from a virtual screening. 34 Both compounds were able to inhibit the replication of different influenza A viruses, Zika-and Ebola virus, as well as, importantly, SARS-CoV-2. 34 Blocking de novo purine nucleotide biosynthesis…”

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confidence: 99%

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Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Huchting

2020

Antivir Chem Chemother

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Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

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confidence: 99%

“…34 Both compounds were able to inhibit the replication of different influenza A viruses, Zika-and Ebola virus, as well as, importantly, SARS-CoV-2. 34 Blocking de novo purine nucleotide biosynthesis…”

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confidence: 99%

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Huchting

2020

Antivir Chem Chemother

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“…The inhibition or knockdown of such host proteins will block the viral replication, providing potential antiviral targets for drug development. Recently, novel and potent inhibitors of human dihydroorotate dehydrogenase (DHODH) were reported as broad-spectrum antiviral agents against RNA viruses including SARS-CoV-2 [94] . DHODH is a rate-limiting enzyme in the de novo pyrimidine nucleotide biosynthetic pathway that catalyzes the stereospecific oxidation of (S)‐dihydroorotate to orotic acid and finally generates uridine and cytosine, providing nucleotide resources for host cells as well as the viruses.…”

Section: Inhibiting the Viral Genome Replicationmentioning

confidence: 99%

“…The in vivo study revealed that S312 had excellent antiviral efficacy in influenza A virus-infected mice. S312/S416 and the approved drugs targeting DHODH (leflunomide/teriflunomide) thus have therapeutic potentials in combating SARS-CoV-2 [ 94 , 95 ].…”

Section: Inhibiting the Viral Genome Replicationmentioning

confidence: 99%

Drug discovery and development targeting the life cycle of SARS-CoV-2

Xu¹,

Jiang²

2021

Fundamental Research

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“…Maraviroc, an antagonist of chemokine receptor type 5 for HIV treatment, presents a typical HTA drug. In a remarkable study published in this journal, Xiong et al reported novel and potent inhibitors of human dihydroorotate dehydrogenase (DHODH) as broad-spectrum antiviral agents against RNA viruses including SARS-CoV-2 (Xiong et al, 2020).…”

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Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase

Jiang

2020

Protein Cell

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The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), referred to as coronavirus disease 2019 (COVID-19), has caused over 13 million infections and over 560,000 deaths worldwide (https://www. who.int/emergencies/diseases/novel-coronavirus-2019/sit uation-reports), posing a significant threat to globally public health and economics. At present, no efficacious antiviral drugs and vaccines have been approved for the prophylaxis or treatment of COVID-19. Tremendous efforts have been made to develop drug and vaccine against SARS-CoV-2. The main protease (Mpro, also called 3CLpro) is an attractive drug target among coronaviruses, and several potent inhibitors of the SARS-CoV-2 3CLpro together with their crystal structures in complex with the protease have been reported (Dai et al., 2020; Jin et al., 2020; Zhang et al., 2020). While the viral RNA-dependent RNA polymerases (RdRp) are well-known broad-spectrum antiviral drug targets, the cryo-electron microscopy structures of the SARS-CoV-2 RdRp and its complex with remdesivir, a promising antiviral candidate developed by Gilead Sciences, validated the efficient inhibition of the viral RNA replication by remdesivir and provided a rational template for drug design to combat SARS-CoV-2 infections (Gao et al., 2020; Wang et al., 2020; Yin et al., 2020). In addition, the trimeric spike protein on the surface of SARS-CoV-2 plays a pivotal role during the viral entry by binding to the peptidase domain of angiotensin-converting enzyme 2 (ACE2), a host cell receptor (Yan et al., 2020). It has been revealed that not only the receptor binding domain which is recognized by ACE2 but also the N-terminal domain of the SARS-CoV-2 spike protein is targeting sites for therapeutic monoclonal antibodies (Chi et al., 2020). Accordingly, both the inhibitors of 3CLpro or RdRp and the antibodies targeting the spike protein provide potential candidates for development of the direct-acting antiviral (DAA) drugs for the treatment of COVID-19.

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Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Cited by 144 publications

References 60 publications

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Drug discovery and development targeting the life cycle of SARS-CoV-2

Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase

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