Substituent size versus metal binding of inhibitors with variants of influenza endonuclease
Year: 2025
Type: article
Abstract: The influenza virus causes a significant burden of illness each year, affecting billions of people worldwide. Although vaccination is the most effective method to prevent seasonal influenza infection, viral escape mechanisms make vaccine composition difficult to predict. Antivirals are crucial for decreasing rates of morbidity and mortality from influenza viral infection. The newest anti-influenza drugs target the RNA-dependent RNA polymerase acidic N-terminal (PA N ) endonuclease, a critical component of influenza viral replication machinery. This study examines the structure of inhibitors of PA N that utilize a hydroxypyridinone-based metal-binding pharmacophore (MBP). Specifically, this report explores how the size of substituent groups impacts the binding conformation and affinity of a series of compounds against both wild-type (WT) and resistance mutant strains, I38T and E23K. Co-crystal structures revealed that the distance between compounds and residue 38 was conserved to maintain ideal interactions, resulting in deviations from ideal coordination geometries at the active site metal centers. This suggests the interactions with residue 38 with each compound is very important and can impact inhibitor potency as a consequence of distortions in the metal binding geometry of the compounds. Binding of inhibitors to the dinuclear active site of influenza endonuclease is modulated by distal interactions to protein residues outside the metal ion coordination sphere. These distal interactions can have a substantial impact on inhibitory activity.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,220
Awards: G1229526393, G1286236842, G1286251239, G1337544421, G1451874870, G1767990418, G223002938, Metal-binding Isosteres for Influenza Endonuclease Inhibitors and Beyond, G2371548206, G2539837713, G2603595557, G2618837358, G262532246, G303061748, G30714459, G3083819904, G315621713, G334911014, G382641700, G419881185, G4202012489, G4235786860, G42916606, G4501827968, G4581610328, G495301720, G498139845, G5570207115, G6173709932, G6188209572, G6206027980, G650090426, G6550344761, G6652958823, G7283024673, G7396808078, G7787287669, G7863156295, G7912248388, G8207748872, G8229677252, G8382000481, G8925327636, G9000054807, G9000263589, A Synchrotron Radiation Structural Biology Resource, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), G911061179, G969889393
OpenAlex ID: W7117746326