2005
DOI: 10.1016/j.bmc.2005.05.065
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Abstract: The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide alpha,beta-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 microM), the ketomethylene isosteres and tripeptide alpha,beta-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 … Show more

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Cited by 93 publications
(9 citation statements)
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References 40 publications
(9 reference statements)
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“…AG7088 itself was found to be inactive in enzyme assays with SARS-CoV M pro ; however, modifications to the peptidomimetic scaffold lead to significant inhibition potencies. [8,9] The electrophilic building block of these active-site-directed inhibitors consists of an a,b-unsaturated ester function, which undergoes nucleophilic attack by the thiol group of the cysteine residue.…”
Section: Introductionmentioning
confidence: 99%
“…AG7088 itself was found to be inactive in enzyme assays with SARS-CoV M pro ; however, modifications to the peptidomimetic scaffold lead to significant inhibition potencies. [8,9] The electrophilic building block of these active-site-directed inhibitors consists of an a,b-unsaturated ester function, which undergoes nucleophilic attack by the thiol group of the cysteine residue.…”
Section: Introductionmentioning
confidence: 99%
“…AG7088, a potent inhibitor of RV 3C pro , was tried but failed to inhibit 3CL pro of SARS-CoV (15), indicating subtle structural differences in their active sites. However, AG7088 analogues and several classes of novel inhibitors have been discovered to combat SARS-CoV by targeting its 3CL pro (16,17).…”
mentioning
confidence: 99%
“…(4), most of the tripeptide-conjugated esters (2 and 4 series) tend to be more active than the corresponding ketomethylene isosteres (1 and 3 series) in inhibiting the protease. For example, the compounds 3a-d and 4a-d with a phenyl group replacing the P1 lactam moiety showed better inhibitory activities (IC 50 = 11-39 µM) than AG7088 (1a) and its analogs (1b-d and 2a-d) (IC 50 ≥ 80 µM) [57]. From computer modeling, the P1 phenylalanine may shift to bind S2 subsite such that the α,β-unsaturated Michael acceptor is beyond the reach of the thiol moiety of Cys145 for forming a covalent linkage.…”
Section: A From High Throughput Screeningmentioning
confidence: 97%
“…A series of analogues were further prepared to improve the inhibitory potencies. Shie et al found that the replacement of the γ-lactam moiety with a phenylalanine side chain increased the inhibitory activity [57]. These conjugated esters were subjected to the inhibition assay using a fluorometric method [25].…”
Section: A From High Throughput Screeningmentioning
confidence: 99%