Inhibition of human cytomegalovirus protease No with monocyclic β-lactams

doi:10.1016/S0960-894X(98)00240-6

Bioorganic & Medicinal Chemistry Letters

Volume 8, Issue 11, 2 June 1998, Pages 1437-1442

https://doi.org/10.1016/S0960-894X(98)00240-6 Get rights and content

Abstract

Monocyclic β-lactams have been identified as potent and selective inhibitors of the human cytomegalovirus protease (HCMV) N_o. Two series of these inhibitors are described, a peptidyl series of compounds and non-peptidic molecules featuring lower molecular weights. The SAR work that lead to the discovery of these inhibitors, together with their synthesis is also disclosed.

A new series of inhibitors of the cytomegalovirus protease is reported. We found that monocyclic β-lactams analogs are potent and selective inhibitors of the title protease.

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Citation Excerpt :
Based on our results, a possible explanation of the lack of substantial difference in the activity of the individual isomers of our compounds is that loss of thiophenol might occur in a concerted fashion along with β-lactam ring opening, a possible pathway suggested earlier.13 In all of the previous studies on structurally similar monocyclic β-lactams (with a leaving group at C4) as inhibitors of both mammalian15–17 and viral16,19 serine proteases, including structures carbamylated16–19 at the lactam nitrogen, the mechanism (proposed or experimentally determined) of enzyme inhibition involves lactam ring opening by the active site serine (covalent complex B, Scheme 3). If formed, either one of the enzyme complexes, enzyme form A, a noncovalent complex, and enzyme form B, a covalent complex (Scheme 3) should experience the chirality at C4.
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Inhibition of human cytomegalovirus protease No with monocyclic β-lactams

Abstract

J. Virol.

J. Virol.

Perspect. Drug Discov. Design

Nature

Nature

Nature

Cell

Inhibition of human cytomegalovirus protease N_o with monocyclic β-lactams