Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme inde novopyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

Abstract

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

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

“…Great efforts from various research groups have been done to discover new agents from several databases by targeting the target Mpro via several virtual screening strategy, 5,6 which consists of pharmacophore, molecule docking, and molecular simulations approaches. As a result, six drugs inhibited Mpro with IC50 values ranging from 0.67 to 21.4 μM.…”

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

“…A series of high-throughput phenotypic cell-based screens have recently identified DHODH inhibition as a potent, broadspectrum antiviral strategy in vitro (Hoffmann et al, 2011;Lucas-Hourani et al, 2013;Luthra et al, 2018;Wang et al, 2011). Furthermore, a DHODH inhibitor was recently shown to suppress SARS-CoV-2 in vitro (Xiong et al, 2020). However, DHODH inhibitors often lose antiviral activity upon extracellular uridine addition due presumably to pyrimidine salvage (Deans et al, 2016).…”

Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase

“…Drug re-purposing means that by examining existing drugs, they will find therapeutic effects on new diseases (Aggarwal et al, 2020;Khan, Jha, et al, 2020;Senathilake et al, 2020). BSAAs are small molecules that can inhibit different infections by blocking the viral replication (Pant et al, 2020;Xiong et al, 2020;. These drugs block the virus or host-related factors and thus prevent the virus from proliferating, then lowering the level of the virus in the body to an extent that the immune system can inhibit their infection (Cui et al, 2020;Ji & Li, 2020).…”