Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy

Abstract

The COVID-19 pandemic has accelerated the development of nucleoside analogs to treat respiratory virus infections, with remdesivir being the first compound to receive worldwide authorization and three other nucleoside analogs (i.e. favipiravir, molnupiravir, and bemnifosbuvir) in the pipeline. Here, we summarize the current knowledge concerning their clinical efficacy in suppressing the virus and reducing the need for hospitalization or respiratory support. We also mention trials of favipiravir and lumicitabine, for influenza and respiratory syncytial virus, respectively. Besides, we outline how nucleoside analogs interact with the polymerases of respiratory viruses, to cause lethal virus mutagenesis or disturbance of viral RNA synthesis. In this way, we aim to convey the key findings on this rapidly evolving class of respiratory virus medication.

Figure 1

Chemical structures of ribavirin, lumicitabine, galidesivir, and brincidofovir. See Figures 2 and 3 for the structures of the other nucleoside analogs discussed in this review.

Figure 2

Favipiravir and molnupiravir: mechanism of RNA virus mutagenesis. After metabolic activation, the (ribosyl-)5′-triphosphate form (abbreviated 'F' and 'M': the ambiguous part in their base is marked in the chemical structure) binds to the viral RdRp active site. Upon two consecutive incorporations, F causes delayed chain termination and RdRp backtracking, while insertion of a single F allows RNA extension. F can replace GTP and, to a lesser degree, (ATP) adenosine-5′-triphosphate, resulting in mutagenesis of the viral RNA. Similarly, M is a closer mimic of (CTP) cytidine-5′-triphosphate than (UTP) uridine-5′-triphosphate, and its incorporation does not halt RNA extension. In the next round, the incorporated M can pair with adenine instead of guanine, inducing insertion of the wrong nucleotide and RNA mutagenesis. The template/primer sequences were taken from references , .

Figure 3

Remdesivir and bemnifosbuvir: inhibitory mechanism toward coronavirus RNA synthesis. Both compounds are prodrugs requiring metabolic activation to their nucleoside-5′-triphosphate form. This metabolite bears one or more key modifications (marked in the chemical structure) and binds to the RdRp active site of the CoV nsp12–nsp7–nsp8 polymerase complex. Being incorporated as an ATP analog, the active form of remdesivir (‘R’) initially allows chain elongation but then stalls RNA synthesis at position + 3. At high NTP concentrations, RNA synthesis continues to the next round, where incorporation of UTP is compromised opposite to R in the template strand. The active form of bemnifosbuvir (‘B’) is incorporated as a GTP analog and causes immediate chain termination. Both inhibitors are proposed to more or less resist excision by nsp14 ExoN. In addition, B and possibly also R can bind to the NiRAN active site in nsp12, to potentially interfere with other reactions in CoV RNA synthesis and modification. The protein structures visualize the SARS-CoV-2 nsp12–nsp7–nsp8 complex with bound RNA (PDB 7ED5) and nsp10–nsp14–RNA complex (PDB 7N0B) . The template/primer sequences were taken from references , .