An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Abstract

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. Here, we show that the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

“…In our study, treatment was administered close to the peak of virus replication in the lungs as indicated by viral loads in bronchoalveolar lavages and the first effects of treatment on clinical signs and virus replication were observed within 12 hours. The efficacy of direct-acting antivirals against acute viral respiratory tract infections typically decreases with delays in treatment initation 18…”

Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir

“…Besides Remdesivir, several drugs of nucleotide analogs, including Favipiravir, Ribavirin, Galidisvir, and EIDD-2801, have been shown to be efficient inhibitors in blocking SARS-CoV-2 replication in cell-based systems (32,33). Like Remdesivir, these nucleotide analogs are proposed to inhibit viral RdRp indirectly through non-obligate RNA chain termination, a mechanism that requires the conversion of the parent compound to the triphosphate active form (30).…”

“…The structure of the template-RTP RdRp complex provides an excellent model to rationalize how these drugs inhibit the SARS-CoV-2 RdRp activity ( Figure 5C). In particular, EIDD-2801 has been shown to be 3-10 times more potent than Remdesivir in blocking SARS-CoV-2 replication (35). The N4 hydroxyl group off the cytidine ring forms an extra hydrogen bond with the side chain of K545.…”

COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies

“…These nonstructural proteins are all potential targets for therapies, which would in theory work against all coronaviruses (Figure 2). 1,8,[10][11][12][13][14][15] The remaining portion of the genome includes interspersed open reading frames for the structural proteins, as well as a number of accessory proteins generally nonessential for replication in tissue culture but capable of suppressing immune responses and enhancing pathogenesis. 10,16…”