210488-97-4

Upstream product

• 1161-13-3 N-Cbz-L-Phe 
• 2488-15-5 N-tert-butoxycarbonyl-L-methionine 
• 82689-12-1 tert-butyl (S)-1-formyl-3-(methylthio)propylcarbamate 
• 104062-76-2 (S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-(methylthio)butanamide 
• 223529-37-1 [(S)-1-(Imidazole-1-carbonyl)-3-methylsulfanyl-propyl]-carbamic acid tert-butyl ester 
• 210488-94-1 (E)-(S)-4-tert-Butoxycarbonylamino-6-methylsulfanyl-hex-2-enoic acid methyl ester 

Relevant academic research and scientific papers

Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication

Human rhinovirus, the chief cause of the common cold, contains a positive-sense strand of RNA which is translated into a large polyprotein in infected cells. Cleavage of the latter to produce the mature viral proteins required for replication is catalyzed in large part by a virally encoded cysteine proteinase (3C(pro)) which is highly selective for -Q~GP- cleavage sites. We synthesized peptidyl derivatives of vinylogous glutamine or methionine sulfone esters (e.g., Boc-Val-Leu-Phe-vGln-OR: R = Me, 1; R = Et, 2) and evaluated them as inhibitors of HRV-14 3C protease (3C(pro)). Compounds 1 and 2 and several related tetra- and pentapeptide analogues rapidly inactivated 3C(pro) with submicromolar IC50 values. Electrospray mass spectrometry confirmed the expected 1:1 stoichiometry of 3C(pro) inactivation by 1, 2, and several other analogues. Compound 2 also proved to be useful for active site titration of 3C(pro) which has not been possible heretofore because of the lack of a suitable reagent. In contrast to 1, 2, and congeners, peptidyl Michael acceptors lacking a P4 residue have greatly reduced or negligible activity against 3C(pro), consistent with previously established structure-activity relationships for 3C(pro) substrates. Hydrolysis of the P1 vinylogous glutamine ester to a carboxylic acid also decreased inhibitory activity considerably, consistent with the decreased reactivity of acrylic acids vs acrylic esters as Michael acceptors. Incorporating a vinylogous methionine sulfone ester in place of the corresponding glutamine derivative in 1 also reduced activity substantially. Compounds 1 and 2 and several of their analogues inhibited HRV replication in cell culture by 50% at low micromolar concentrations while showing little or no evidence of cytotoxicity at 10-fold higher concentrations. Peptidyl Michael acceptors and their analogues may prove useful as therapeutic agents for pathologies involving cysteine proteinase enzymes.