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HGNC Genes

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

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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