Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

There are no SARS-CoV-2 protein terms in the subcorpus


SARS-CoV-2 Proteins
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    The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models

    Authors: Kim M Stegmann; Antje Dickmanns; Sabrina Gerber; Vella Nikolova; Luisa Klemke; Valentina Manzini; Denise Schloesser; Cathrin Bierwirth; Julia Freund; Maren Sitte; Raimond Lugert; Gabriela Salinas; Dirk Goerlich; Bernd Wollnik; Uwe Gross; Matthias Dobbelstein

    doi:10.1101/2020.07.18.210013 Date: 2020-07-20 Source: bioRxiv

    The search for successful therapies of infections with the coronavirus SARS-CoV-2 is ongoing. We tested inhibition of host cell nucleotide synthesis as a promising strategy to decrease the replication of SARS-CoV-2-RNA, thus diminishing the formation of virus progeny. Methotrexate ( MTX HGNC) is an established drug for cancer MESHD therapy and to induce immunosuppression. The drug inhibits dihydrofolate reductase and other enzymes required for the synthesis of nucleotides. Strikingly, the replication of SARS-CoV-2 was inhibited by MTX HGNC in therapeutic concentrations around 1 M, leading to more than 1000-fold reductions in virus progeny in Vero C1008 (Vero E6) as well as Calu-3 cells. Virus replication was more sensitive to equivalent concentrations of MTX HGNC than of the established antiviral agent remdesivir. MTX HGNC strongly diminished the synthesis of viral structural proteins and the amount of released virus RNA. Virus replication and protein synthesis were rescued by folinic acid (leucovorin) and also by inosine, indicating that purine depletion is the principal mechanism that allows MTX HGNC to reduce virus RNA synthesis. The combination of MTX HGNC with remdesivir led to synergistic impairment of virus replication, even at 300 nM MTX HGNC. The use of MTX HGNC in treating SARS-CoV-2 infections MESHD SARS-CoV-2 infections MESHD still awaits further evaluation regarding toxicity MESHD and efficacy in infected organisms, rather than cultured cells. Within the frame of these caveats, however, our results raise the perspective of a two-fold benefit from repurposing MTX HGNC for treating COVID-19 MESHD. Firstly, its previously known ability to reduce aberrant inflammatory responses might dampen respiratory distress. In addition, its direct antiviral activity described here would limit the dissemination of the virus. SIGNIFICANCEO_LIMTX is one of the earliest cancer drugs to be developed, giving rise to seven decades of clinical experience. It is on the World Health Organizations List of Essential Medicines, can be administered orally or parenterally, and its costs are at single digit {euro} or $ amounts/day for standard treatment. In case of its successful further preclinical evaluation for treating SARS-CoV-2 infection MESHDs, its repurposing to treat COVID-19 MESHD would thus be feasible, especially under low-resource conditions. C_LIO_LIAdditional drugs exist to interfere with the synthesis of nucleotides, e.g. additional folate antagonists, inhibitors of GMP synthetase, or inhibitors of dihydroorotate dehydrogenase HGNC ( DHODH HGNC). Such inhibitors have been approved as drugs for different purposes and might represent further therapeutic options against infections with SARS-CoV-2 C_LIO_LIRemdesivir is currently the most established drug for treating COVID-19 MESHD. Our results argue that MTX HGNC and remdesivir, even at moderate concentrations, can act in a synergistic fashion to repress virus replication to a considerably greater extent than either drug alone. C_LIO_LI COVID-19 MESHD, in its severe forms, is characterized by pneumonia and acute respiratory distress syndrome, and additional organ involvements. These manifestations are not necessarily a direct consequence of virus replication and cytopathic effects, but rather a result of an uncontrolled inflammatory and immune response. Anti-inflammatory drugs such as glucocorticoids are thus being evaluated for treating COVID-19 MESHD. However, this bears the risk of re-activating virus spread by suppressing a sufficient and specific immune response. In this situation, it is tempting to speculate that MTX HGNC might suppress both excessive inflammation as well as virus replication at the same time, thus limiting both the pathogenesis of pneumonia and also the spread of virus within a patient. C_LI

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

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

    doi:10.1101/2020.03.11.983056 Date: 2020-03-12 Source: bioRxiv

    Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2 MESHD. 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 HGNC) 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 HGNC, 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 HGNC is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH HGNC knocking-out cells. We also proposed the drug combination of DAA and HTA HGNC was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases MESHD 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 MESHD 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 MESHD circulating worldwide, no matter such viruses mutate or not.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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