Selective covalent targeting of SARS-CoV-2 main protease by enantiopure chlorofluoroacetamide

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) is a promising target for...

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

“… 81 , 102 Compound 40 (IC 50 = 0.056 μM) inhibited M PRO in a time-dependent manner, indicating an irreversible mode of action with a k i value of 1.34 μM and K inact / k i value of 4167 M –1 s –1 . 82 …”

“…α-Haloacetamide derivatives are also irreversible SARS-CoV-2 M PRO inhibitors. In particular, enzymatic kinetic studies for compounds 38 (IC 50 = 0.43 μM, EC 50 = 2.05 μM, and ratio of EC 50 /IC 50 = 2.76) and 39 (IC 50 = 0.08 μM, EC 50 = 2.15 μM, and ratio of EC 50 /IC 50 = 26.87) proposed a two-step process for inhibition of SARS-CoV-2 M PRO : the first step is a reversible binding adduct, and the second step is an irreversible binding complex; these results were in agreement with the expected mechanism of action in which compounds 38 and 39 form a covalent bond with the catalytic Cys 145 . , Compound 40 (IC 50 = 0.056 μM) inhibited M PRO in a time-dependent manner, indicating an irreversible mode of action with a k i value of 1.34 μM and K inact / k i value of 4167 M –1 s –1 …”

“…In silico simulation ascribed the higher activity of this stereoisomer to its more stable and reactive conformation within the active site. 82 …”

“…Remarkably, biological inhibition assays showed that the stereochemistry of the two asymmetric carbons plays a crucial role: of the four possible stereoisomers, ( R,R )- cis - 40 was the only one with strong inhibitory activity against SARS-CoV-2 M PRO , with an outstanding IC 50 of 0.056 μM and a remarkable K inact / k i value of 4.2 × 10 3 M –1 s –1 . In silico simulation ascribed the higher activity of this stereoisomer to its more stable and reactive conformation within the active site …”

Redox stress in COVID-19: Implications for hematologic disorders

“…Covalent modification of cysteines using electrophilic warheads have been utilized to develop potent inhibitors in many context (reviewed in [ 86 ]). Indeed, targeting Cys145 with the electrophiles chlorofluoroacetamide [ 87 ], α-ketoamides [ 88 ], ketones [ [89] , [90] , [91] , [92] ], vinyl sulfones [ 93 ], nitriles [ 94 , 95 ], and aldehydes [ [96] , [97] , [98] ] showed strong potency against the enzymatic activity of MPro. In addition to covalently labeling the catalytic cysteine of MPro, the oxidation statuses of cysteines in the mature virion have been targeted with specific probes.…”