TDI-015051 is a highly potent, specific inhibitor of SARS-CoV-2 NSP14 RNA cap methyltransferase with Kd of 61 pM and IC50 of <0.15 nM, inhibits viral mRNA translation.
TDI-015051 occupies the SAH-stabilized cap-binding pocket of NSP14, forming additional stabilizing interactions.
TDI-015051 inhibits SARS-CoV-2 infection with an EC50 of 11.4 nM in Huh-7.5 cells, with no cytotoxicity up to 3 uM, co-treatment of Huh-7.5 cells with 5 µM DZNeP further potentiated TDI-015051 antiviral activity (EC50 = 0.8 nM).
TDI-015051 potently inhibits viral infection in the adenocarcinoma-derived alveolar basal epithelial cell line A549 expressing ACE2 and TMPRSS2 (EC50 = 64.7 nM), TDI-015051(>4 nM) also prevented SARS-CoV-2 viral replication in human primary small airway epithelial cells grown at the air–liquid interface.
NSP14(V290A), NSP14(N306K), NSP14(P335S) and NSP14(H424R) plaque-purified viruses showed resistance to TDI-015051 with EC50 values elevated 40-fold or more relative to wild type.
TDI-015051 inhibits NSP14 of other hCoVs with IC50 of 1.7 nM, 2.6 nM or 3.6 nM for NSP14 of alphacoronaviruses α-hCoV-NL63, α-hCoV-229E, and betacoronavirus β-hCoV-MERS, resepctively.
TDI-015051 inhibits hCoV-NL63 and hCoV-229E infection in Huh-7.5 cells with EC50 of 0.12 µM and 3.7 µM, respectively.
TDI-015051 does not inhibit the human RNA guanine-7 methyltransferase (RNMT) in complex with its protein cofactor RAM29 nor NS5 MTase from Zika virus.
TDI-015051 (150-500 mg/kg, orally) reduces SARS-CoV-2 viral lung burden in a K18-hACE2 transgenic mouse model.
