269411-42-9Relevant articles and documents
Chemical Evolution of Antivirals Against Enterovirus D68 through Protein-Templated Knoevenagel Reactions
Tauber, Carolin,Wamser, Rebekka,Arkona, Christoph,Tügend, Marisa,Abdul Aziz, Umer Bin,Pach, Szymon,Schulz, Robert,Jochmans, Dirk,Wolber, Gerhard,Neyts, Johan,Rademann, J?rg
supporting information, p. 13294 - 13301 (2021/05/10)
The generation of bioactive molecules from inactive precursors is a crucial step in the chemical evolution of life, however, mechanistic insights into this aspect of abiogenesis are scarce. Here, we investigate the protein-catalyzed formation of antivirals by the 3C-protease of enterovirus D68. The enzyme induces aldol condensations yielding inhibitors with antiviral activity in cells. Kinetic and thermodynamic analyses reveal that the bioactivity emerges from a dynamic reaction system including inhibitor formation, alkylation of the protein target by the inhibitors, and competitive addition of non-protein nucleophiles to the inhibitors. The most active antivirals are slowly reversible inhibitors with elongated target residence times. The study reveals first examples for the chemical evolution of bio-actives through protein-catalyzed, non-enzymatic C?C couplings. The discovered mechanism works under physiological conditions and might constitute a native process of drug development.
Substituted benzamide inhibitors of human rhinovirus 3C protease: Structure-based design, synthesis, and biological evaluation
Reich, Siegfried H.,Johnson, Theodore,Wallace, Michael B.,Kephart, Susan E.,Fuhrman, Shella A.,Worland, Stephen T.,Matthews, David A.,Hendrickson, Thomas F.,Chan, Fora,Meador III, James,Ferre, Rose Ann,Brown, Edward L.,DeLisle, Dorothy M.,Patick, Amy K.,Binford, Susan L.,Ford, Clifford E.
, p. 1670 - 1683 (2007/10/03)
A series of nonpeptide benzamide-containing inhibitors of human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation of these inhibitors are reported. A Michael acceptor was combined with a benzamide core mimicking the P1 recognition element of the natural 3CP substrate, α,β-Unsaturated cinnamate esters irreversibly inhibited the 3CP and displayed antiviral activity (EC50 0.60/μM, HRV-16 infected H1-HeLa cells). On the basis of cocrystal structure information, a library of substituted benzamide derivatives was prepared using parallel synthesis on solid support. A 1.9 A? cocrystal structure of a benzamide inhibitor in complex with the 3CP revealed a binding mode similar to that initially modeled wherein covalent attachment of the nucleophilic cysteine residue is observed. Unsaturated ketones displayed potent reversible inhibition but were inactive in the cellular antiviral assay and were found to react with nucleophilic thiols such as DTT.
