EIDD-2801 is an orally bioavailable prodrug of EIDD-1931, which has a broad-spectrum antiviral activity against 39 multiple coronaviruses, including SARS-CoV2, MERS-CoV, SARS-CoV. and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor.
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. EIDD-2801, an orally bioavailable prodrug of NHC (β-D-N4-hydroxycytidine-5′-isopropyl ester), has broad spectrum antiviral activity against influenza virus and multiple coronaviruses, such as SARS-CoV-2, MERS-CoV, SARS-CoV. Beginning on 3 days post-infection (dpi), body weight loss compared to vehicle treatment was significantly diminished (50 mg/kg) or prevented (150, 500 mg/kg) with EIDD-2801 prophylaxis in C57BL/6 mice. Lung hemorrhage was also significantly reduced 5 dpi with 500 mg/kg EIDD-2801 treatment. Interestingly, there was a dose-dependent reduction in SARS-CoV lung titer with significant differences among the vehicle, 150 mg/kg (P = 0.03) and 500 mg/kg (P = 0.006) groups suggesting that prophylactic orally administered EIDD-2801 was robustly antiviral and able to prevent SARS-CoV replication and disease. Similar to SARS-CoV data, all doses of prophylactic EIDD-2801 (50, 150 and 500 mg/kg) protected hDPP4 288/330 mice from significant body weight loss, lung hemorrhage, and virus replication which was undetectable regardless of drug dose following intranasal infection with 5E+04 PFU mouse-adapted MERS-CoV. Interestingly, when viral genomic RNA was quantified in paired samples of lung tissue, EIDD-2801 significantly reduced quantities of viral RNA in an initiation time-dependent manner for all groups except for +48 hours. Collectively, EIDD-2801 robustly reduces MERS-CoV infectious titers, viral RNA, and pathogenesis under both prophylactic and early therapeutic conditions. Lastly, the EIDD-2801 dose-dependent mutagenesis of viral RNA correlated with an increase in codon change frequency, including stop codons, in mice where treatment was initiated 12 hours or before[1].
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