Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2

Schultz et al., Nature, doi:10.1038/s41586-022-04482-x, Feb 2022
In vitro and mouse study showing synergistic antiviral effects when combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues against SARS-CoV-2. Authors screened 18 thousand drugs and validated 122 with antiviral activity against SARS-CoV-2 in human respiratory cells, including remdesivir, molnupiravir, camostat, nafamostat, and artesunate. Pyrimidine biosynthesis inhibitors such as brequinar and BAY-2402234 (DHODH inhibitors) showed modest antiviral activity alone but demonstrated strong synergy when combined with molnupiravir or remdesivir. In mouse models infected with the SARS-CoV-2 Beta variant, the combination of molnupiravir with brequinar showed significantly reduced viral titers (up to 4-log reduction) and decreased lung inflammation compared to either drug alone. The synergistic effect was observed in multiple cell types and was effective against multiple SARS-CoV-2 variants.
Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov show increased risk of liver injury, and Negru, Cheng, Mohammed show increased risk of cardiac disorders with remdesivir.
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Study covers molnupiravir, remdesivir, camostat, nafamostat, artemisinin, and TMPRSS2 inhibitors.
Schultz et al., 7 Feb 2022, USA, peer-reviewed, 22 authors. Contact: dschultz@pennmedicine.upenn.edu, mfrieman@som.umaryland.edu, cherrys@pennmedicine.upenn.edu.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: Article Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2 https://doi.org/10.1038/s41586-022-04482-x Received: 22 October 2021 Accepted: 26 January 2022 Published online: 7 February 2022 David C. Schultz1 ✉, Robert M. Johnson2,8, Kasirajan Ayyanathan3,8, Jesse Miller3,8, Kanupriya Whig1, Brinda Kamalia1, Mark Dittmar3, Stuart Weston2, Holly L. Hammond2, Carly Dillen2, Jeremy Ardanuy2, Louis Taylor2, Jae Seung Lee3, Minghua Li3, Emily Lee4, Clarissa Shoffler5, Christopher Petucci5, Samuel Constant6, Marc Ferrer4, Christoph A. Thaiss7, Matthew B. Frieman2 ✉ & Sara Cherry1,3,7 ✉ Check for updates The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half1 (https://www.who.org/). Individuals with SARS-CoV-2 infection typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes2. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. 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. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward. SARS-CoV-2 is a coronavirus, which is a family of single-stranded positive-sense RNA viruses, at least seven of which infect humans. RNA viruses including coronaviruses replicate using a virally encoded RNA-dependent RNA polymerase (RdRp), and nucleoside analogues, which are incorporated by the RdRp into the growing viral RNA chain, are a large class of approved direct-acting antivirals3. Depending on the analogue, incorporation can lead to chain termination or mutagenesis, ultimately inhibiting viral replication4. RdRps have conserved structures, and thus nucleoside analogues can show broad activity across related and unrelated viruses5,6. Therefore, repurposing efforts have identified nucleoside analogues that are active against newly emerging viruses, and such efforts have discovered that the nucleoside analogue remdesivir inhibits SARS-CoV-2 replication, becoming the first approved antiviral therapeutic against this novel coronavirus7,8. As all viruses, including SARS-CoV-2, are dependent on diverse cellular factors and metabolic products for their replication, the identification of host-directed antivirals also shows promise. In particular, host nucleoside biogenesis is required for viral replication as RNA viruses require high levels of nucleoside triphosphates for their growth. Widespread efforts are underway to identify essential..
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