Targeting SARS-CoV-2 nonstructural protein 3: Function, structure, inhibition, and perspective in drug discovery

Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target

“…1 H NMR (400 MHz, DMSOd 6 ) δ ppm 1.46−1.62 (m, 4H), 1.75−1.84 (m, 2H), 2.35−2.42 (m, 2H), 2.44−2.48 (m, 2H), 2.65−2.71 (m, 2H), 2.90−3.03 (m, 2H), 3.07−3.15 (m, 1H), 3.17−3.26 (m, 1H), 3.57 (s, 3H), 3.84 (s, 3H), 5.69 (m, 2H), 10.99 (s, 1H). 13 (24). In a roundbottom flask, 31.5 mg (0.78 mmol) of sodium hydroxide was dissolved in deionized water and 56.9 mg (0.15 mmol) of compound 15r was added.…”

“…17,20 The discovered SARS-CoV-2 Mac1 inhibitors have also been recently discussed in reviews. 23,24 The majority of the compounds reached low-mid μM potency, though a few reached sub-μM IC 50 's, and in general, they lacked the properties allowing cell permeability and subsequent validation of SARS-CoV-2 Mac1 as a pharmacological target. Using a recently developed robust protein fluorescence resonance energy transfer (FRET)-based assay, 21,25 we performed high-throughput screening of compounds to identify novel inhibitors of SARS-CoV-2 Mac1.…”

“…Initial compounds targeting virus macrodomains have been described for alphaviruses , and coronaviruses. − These efforts have used both screening of compound libraries, ,, in crystallo fragment screening to discover early small inhibitors, and further development to produce more potent compounds. , The discovered SARS-CoV-2 Mac1 inhibitors have also been recently discussed in reviews. , The majority of the compounds reached low-mid μM potency, though a few reached sub-μM IC 50 ’s, and in general, they lacked the properties allowing cell permeability and subsequent validation of SARS-CoV-2 Mac1 as a pharmacological target.…”

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

“…The high mutation frequency of spike protein is responsible for the escape of SARS-CoV-2 from the vaccines. Unlike spike protein, the non-structural proteins (such as 3CL pro (nsp5) and PL pro (nsp3)) remain conserved among coronavirus functional proteins and show much lower mutation frequency in natural SARS-CoV- 2 variants 7,8 . The high conservativeness makes 3CL pro and PL pro attractive drug targets.…”

“…However, these reported compounds only show enzymatic activity from μM to sub-μM. Except for F0213, there is no drug- like PL pro inhibitors have reported in vivo antiviral efficacy in SARS-CoV-2 infected animal model 8,19,33 . In this study, we synthesized a series of novel PL pro inhibitors and evaluated their activities.…”