Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV-2 to Low-Nanomolar Antiviral Potency.
Chun-Hui ZhangKrasimir A SpasovRaquel A ReillyKlarissa HollanderElizabeth A StoneJoseph A IppolitoMaria-Elena LiosiMaya G DeshmukhJulian Tirado-RivesShuo ZhangZhuobin LiangScott J MillerFarren J IsaacsBrett D LindenbachKaren S AndersonWilliam L JorgensenPublished in: ACS medicinal chemistry letters (2021)
Non-covalent inhibitors of the main protease (Mpro) of SARS-CoV-2 having a pyridinone core were previously reported with IC50 values as low as 0.018 μM for inhibition of enzymatic activity and EC50 values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of Mpro and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC50 values as low as 0.080 μM, while remdesivir yields values of 0.5-2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds 19 and 21 are particularly promising as potential therapies for COVID-19, featuring IC50 values of 0.044-0.061 μM, EC50 values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- induced apoptosis
- dna methylation
- stem cells
- gene expression
- ultrasound guided
- nitric oxide
- single cell
- molecular dynamics simulations
- oxidative stress
- cell proliferation
- molecular dynamics
- cell therapy
- density functional theory
- mesenchymal stem cells
- hydrogen peroxide
- cell cycle arrest
- risk assessment
- molecular docking
- endoplasmic reticulum stress
- protein protein