The 3C-like proteinase (3CLpro) of severe acuterespiratory syndrome (SARS) coronavirus is a key target forstructure-based drug design against this viral infection. Theenzyme recognizes peptide substrates with a glutamine residueat the P1 site. A series of keto-glutamine analogues with aphthalhydrazido group at the α-position were synthesized andtested as reversible inhibitiors against SARS 3CLpro. Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based“warheads” generated significantly better inhibitors (4a−c,8a−d) with IC50 values ranging from 0.60 to 70 μM.
