SARS CoV ja sen kymotrypsiinin kaltaisen proteaasin (3CLPro) estäjien kehittely

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Select item 302174951.

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses.

Lim L, Gupta G, Roy A, Kang J, Srivastava S, Shi J, Song J.

Prog Biophys Mol Biol. 2019 May;143:52-66. doi: 10.1016/j.pbiomolbio.2018.08.009. Epub 2018 Sep 11. Review.

Coronavirus 3C-like and Flavivirus NS2B-NS3 proteases utilize the chymotrypsin fold to harbor their catalytic machineries but also contain additional domains/co-factors. Over the past decade, we aimed to decipher how the extra domains/co-factors mediate the catalytic machineries of SARS 3C-like, Dengue and Zika NS2B-NS3 proteases by characterizing their folding, structures, dynamics and inhibition with NMR, X-ray crystallography and MD simulations, and the results revealed: 1) the chymotrypsin fold of the SARS 3C-like protease can independently fold, while, by contrast, those of Dengue and Zika proteases lack the intrinsic capacity to fold without co-factors. 2) Mutations on the extra domain of SARS 3C-like protease can transform the active catalytic machinery into the inactive collapsed state by structurally-driven allostery. 3) Amazingly, even without detectable structural changes, mutations on the extra domain are sufficient to either inactivate or enhance the catalytic machinery of SARS 3C-like protease by dynamically-driven allostery. 4) Global networks of correlated motions have been identified: for SARS 3C-like protease, N214A inactivates the catalytic machinery by decoupling the network, while STI/A and STIF/A enhance by altering the patterns of the network. The global networks of Dengue and Zika proteases are coordinated by their NS2B-cofactors. 5) Natural products were identified to allosterically inhibit Zika and Dengue proteases through binding a pocket on the back of the active site. Therefore, by introducing extra domains/cofactors, nature develops diverse strategies to regulate the catalytic machinery embedded on the chymotrypsin fold through folding, structurally- and dynamically-driven allostery, all of which might be exploited to develop antiviral drugs.

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Select item 256141102.

Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors.

Shimamoto Y, Hattori Y, Kobayashi K, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K.

Bioorg Med Chem. 2015 Feb 15;23(4):876-90. doi: 10.1016/j.bmc.2014.12.028. Epub 2014 Dec 20.

The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.

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Select item 193624793.

New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CL(pro) inhibitors.

Regnier T, Sarma D, Hidaka K, Bacha U, Freire E, Hayashi Y, Kiso Y.

Bioorg Med Chem Lett. 2009 May 15;19(10):2722-7. doi: 10.1016/j.bmcl.2009.03.118. Epub 2009 Mar 28.

A series of trifluoromethyl, benzothiazolyl or thiazolyl ketone-containing peptidic compounds as SARS-CoV 3CL protease inhibitors were developed and their potency was evaluated by in vitro protease inhibitory assays. Three candidates had encouraging results for the development of new anti-SARS compounds

 https://www.ncbi.nlm.nih.gov/pmc/?term=19362479%5BPMID%5D&report=imagesdocsum

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Select item 162506324.

Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors.

Ghosh AK, Xi K, Ratia K, Santarsiero BD, Fu W, Harcourt BH, Rota PA, Baker SC, Johnson ME, Mesecar AD.

J Med Chem. 2005 Nov 3;48(22):6767-71.

Design, synthesis, and biological evaluation of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease (SARS-3CLpro) inhibitors for severe acute respiratory syndrome coronavirus (SARS-CoV) are described. These inhibitors exhibited antiviral activity against SARS-CoV in infected cells in the micromolar range. An X-ray crystal structure of our lead inhibitor (4) bound to SARS-3CLpro provided important drug-design templates for the design of small-molecule inhibitors.

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