ABSTRACT
Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A(H1N1)pdm09, A(H3N2), A(H5N1), and A(H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119G/V, NA-H274Y, NA-I122L/N, and NA-R150K. Broadly, AV5080 showed enhanced in vitro efficacy when compared with oseltamivir and/or zanamivir. Reduced AV5080 inhibition was determined for influenza A viruses with NA-E119G and NA-R292K, and for B/Victoria-lineage viruses with NA-I122N/L and B/Yamagata-lineage virus with NA-R150K. Molecular modeling suggested loss of the short hydrogen bond to the carboxyl group of AV5080 affected inhibition of NA-R292K viruses, whereas loss of the salt bridge with the guanidine group of AV5080 affected inhibition of NA-E119G. The resistance profiles and predicted binding modes of AV5080 and zanamivir are most similar, but dissimilar to those of oseltamivir, in part because of a guanidine moiety compensatory binding effect. Overall, our data suggests that AV5080 is a promising orally-dosed NAI that exhibited similar or superior in vitro efficacy against viruses with reduced or highly reduced inhibition phenotypes with respect to currently approved NAIs.
Subject(s)
Herpesvirus 1, Cercopithecine , Influenza A Virus, H1N1 Subtype , Influenza A Virus, H5N1 Subtype , Influenza A Virus, H7N9 Subtype , Influenza, Human , Humans , Antiviral Agents/pharmacology , Drug Resistance, Viral/genetics , Enzyme Inhibitors/pharmacology , Guanidine/metabolism , Guanidines/metabolism , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H3N2 Subtype , Influenza, Human/virology , Neuraminidase/genetics , Oseltamivir/pharmacology , Zanamivir/pharmacologyABSTRACT
In our ongoing efforts to identify baloxavir resistance markers, we demonstrated that the influenza A polymerase acidic (PA) protein E23R substitution is genetically stable, increases baloxavir EC50 values (13- to 19-fold vs. wild-type), synergizes with PA I38T, and only modestly decreases viral fitness. E23R is, therefore, a potential threat to baloxavir treatment efficacy.
