Potent inhibition of norovirus 3CL protease by peptidyl α-ketoamides and α-ketoheterocycles

Abstract

A series of structurally-diverse α-ketoamides and α-ketoheterocycles was synthesized and subsequently investigated for inhibitory activity against norovirus 3CL protease in vitro, as well as anti-norovirus activity in a cell-based replicon system. The synthesized compounds were found to inhibit norovirus 3CL protease in vitro and to also exhibit potent anti-norovirus activity in a cell-based replicon system.

Structural and inhibitor studies of norovirus 3C-like proteases

“…Thus there is an urgent and unmet need for the discovery and development of antiviral therapeutics for the prevention and treatment of norovirus infection. Our group has focused on the discovery and development of small molecules as anti-norovirus therapeutics with enzyme and /or cell based assay systems (Dou et al, 2011a; Dou et al, 2011b; Dou et al, 2012; Dou et al, 2011c; Kim et al, 2011; Mandadapu et al, 2013a; Mandadapu et al, 2012; Mandadapu et al, 2013b; Pokhrel et al, 2012; Tiew et al, 2011). …”

“…In addition, the design, synthesis, and evaluation of transition state inhibitors of norovirus 3CLpro, including GC376 (a dipeptidyl compound), was recently reported by our group (Kim et al, 2012; Mandadapu et al, 2012; Tiew et al, 2011). In this study, the proteolytic activities of three 3CLpro from Norwalk virus (NV, genogroup I), MD145 (genogroup II) and murine norovirus-1 (MNV-1, genogroup V) were optimized for a fluorescence resonance energy transfer (FRET) assay, and compared for the inhibitory activities of a synthetic protease inhibitor (GC376).…”

Repurposing of rutin for the inhibition of norovirus replication

“…To date, three of the nine proteins encoded by the (? )-sense, single-stranded RNA genome have been researched extensively for their potential as antiviral targets [1]: the capsid protein VP1 [10,33], the protease [22,28,42], and the RNA-dependent RNApolymerase (RdRp) [6,36,49]. In the absence of a robust HuNoV cell culture system [21], murine NoV (MNV) has proved to be an attractive and widely used surrogate virus for HuNoV, including for drug development efforts [37].…”

Palladium Catalyzed Oxidation of Ynamides Using Dimethyl Sulfoxide as Oxidant: A Facile Way to Synthesizeα-Ketoamide Derivatives

“…α-酮酰胺化合物是一类重要的有机合成中间体, 并 且用于疟疾蛋白酶抑制剂 [1] 、钙蛋白酶抑制剂 [2] 、诺如 病毒蛋白酶抑制剂 [3] 、登革热病毒蛋白酶抑制剂 [4] 、组 织蛋白酶 S 抑制剂 [5] 、胰脂肪酶抑制剂 [6] 的分子结构设 计中. 治疗丙型肝炎的新药 Boceprevir [7] 和 Telaprevir [8] 及治疗湿疹的药物 Tacrolimus (FK506) [9] 均含有 α-酮酰 胺结构单元(图 1).…”