Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection

Abstract

The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only ∼90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened ∼18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…Although not a certainty, these drugs may also synergize with MPV, as both drugs target the SARS-CoV-2 RNA-dependent RNA polymerase ( 2 , 104 ), albeit with different biochemical mechanisms ( 19 , 105 ). Indeed, similar synergistic activity of RDV and MPV drug pairs was reported in two studies ( 77 , 86 ). Of the 14 drugs listed, 9 are approved by the FDA, and 2 are used in Japan.…”

“…Viral polymerases are clearly good targets for DAAs, and 43 drugs have been reported to synergize with the polymerase inhibitors MPV and/or RDV. Given the goal of developing a regimen for outpatient use, we highlight in Table 1 oral and inhaled drugs that synergistically impede SARS-CoV-2 in Calu3 epithelial cells in conjunction with MPV, the oral polymerase inhibitor ( 18 – 21 ): three orally available drugs, the pyrimidine biosynthesis inhibitors BAY-2402234 and brequinar ( 77 ) and the HIV (aspartic) protease inhibitor nelfinavir ( 80 ), and the inhaled drug interferon alpha. We also list in Table 1 drugs reported to synergize in Calu3 cells with RDV.…”

“…Two other agents appeared to synergize with RDV in Calu3 cells but were tested only at two doses: the approved oral drug mefloquine ( 98 ) and the investigational drug brilacidin ( 88 ). Of the pairs in Table 1 , only the combination of MPV plus brequinar has been tested in an animal model, where it reduced viral loads and lung pathology favorably compared to either drug alone ( 77 ). Brequinar has demonstrated synergy against HCV in combination with sofosbuvir, an orally available HCV polymerase inhibitor ( 80 ).…”

DCcov: Repositioning of drugs and drug combinations for SARS-CoV-2 infected lung through constraint-based modeling

“…Alterations in the expression of genes of the pyrimidine metabolism were significantly higher in the A549, suggesting a response that could be specific to this cell line. Additionally, using pyrimidine biosynthesis inhibitors on SARS-CoV-2-infected mouse models, reduced individually viral infectivity, and reduced lung inflammation when used in combinations (Schultz et al, 2021).…”

Generative AI Design and Exploration of Nucleoside Analogs

“…The Parent Nucleosides consist of adenosine, guanosine, cytidine, thymidine, and uridine. The SARS-CoV-2 Nucleosides were identified by Schultz et al (49) as a group of fifteen nucleoside analogs that show in vitro activity against SARS-CoV-2. The SARS-CoV-2 Nucleosides include: Molnupiravir, Remdesivir, 6-Mercaptopurine, 6-Thio-dG, 6-Thiopurine riboside, 8-Azaguanine, Azathiopurine, BCNA, Cloturin, Flufylline, Gemcitabine, GS-441524, Thiamiprine, Thioguanine, and Tubercidin.…”