Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action.
The related 3C and 3C-like proteinase (3C(pro) and 3CL(pro)) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C(pro). Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C(pro) with K(ic)s of 120-240nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C(pro) and SARS 3CL(pro), confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C(pro).
Huitema
Carly
C
Department of Microbiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3.
Zhang
Jianmin
J
Yin
Jiang
J
James
Michael N G
MN
Vederas
John C
JC
Eltis
Lindsay D
LD
D000086042:3C Viral Proteases; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004952:Esters; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D000086782:Coronavirus 3C Proteases