Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

Abstract

Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

“…The solvent was evaporated under reduced pressure and compounds 4e was used in the next step without further purification. 46,47 Synthesis of sulfonyl compounds 5a-h. General procedure. A solution of compound 4e (100 mg, 0.32 mmol) in dry THF (3 mL) treated with triethyl amine (0.13 mL, 0.64 mmol) followed by added appropriate sulfonyl chloride (63 mg, 0.32 mmol) while stirring and continue the reaction for 12 h. Residue was dissolved in ethyl acetate (50 mL) and washed with 5% HCl (2 × 20 mL) and saturated NaCl (20 mL), dried over sodium sulfate, filtered and concentrated to yield crude product, which is purified by column chromatography yield the corresponding esters 5a-h as colorless oils.…”

Norovirus antivirals: Where are we now?

“…Another subclass of TS inhibitors includes macrocyclic compounds which are structurally modified versions of the aforementioned peptide‐based TS inhibitors. These macrocyclic compounds were originally designed to improve the membrane permeability and oral bioavailability of TS inhibitors to increase their suitability for the clinical application .…”

“…compound 17 [2.3.12]), and oxazolidinone‐based (EC 50 range, 6.7‐17.5 μM; e.g. compound 9 [2.3.13]) variants against the Norwalk replicon. Although none of the macrocyclic TS inhibitors have reached the potency achieved by the peptide‐based TS inhibitors, several macrocyclic variants display broad‐spectrum antiviral activity against members of the picornavirus‐like supercluster similar to that of Rupintrivir .…”

Potent protease inhibitors of deadly lagoviruses: rabbit hemorrhagic disease virus and European brown hare syndrome virus

“…This virus polyprotein processing by 3CLpro is an essential step in virus replication and is thus considered a promising target for drug discovery for viruses that encode 3CLpro, such as caliciviruses and coronaviruses. We have previously reported potent 3CLpro inhibitors of caliciviruses including human norovirus (Damalanka et al, 2016; Damalanka et al, 2017; Damalanka et al, 2018; Galasiti Kankanamalage et al, 2017a; Galasiti Kankanamalage et al, 2015; Galasiti Kankanamalage et al, 2019; Kim et al, 2012; Mandadapu et al, 2013a; Mandadapu et al, 2013b; Mandadapu et al, 2012; Rathnayake et al, 2020a; Weerawarna et al, 2016) and feline calicivirus (Kim et al, 2015) and of coronaviruses such as feline infectious peritonitis virus (FIPV) (Kim et al, 2016; Pedersen et al, 2018), MERS-CoV (Rathnayake et al, 2020b), MERS-CoV (Rathnayake et al, 2020b) and SARS-CoV-2 (Dampalla et al, 2021a; Dampalla et al, 2021b). In this study, we established a fluorescence resonance energy transfer (FRET) assay and a cell-based reporter assay to evaluate 3CLpro inhibitors and identified potent compounds against RHDV1 and 2 and EBSHV.…”