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Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

TS. Corrigan, LM. Lotti Diaz, SE. Border, SC. Ratigan, KQ. Kasper, D. Sojka, P. Fajtova, CR. Caffrey, GS. Salvesen, CA. McElroy, CM. Hadad, Ö. Doğan Ekici

. 2020 ; 35 (1) : 1387-1402. [pub] -

Language English Country Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc21011799

Grant support
R01 GM099040 NIGMS NIH HHS - United States

Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and -6, and aza-Asn derivatives that inhibited S. mansoni and I. ricinus legumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initial in vitro selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

References provided by Crossref.org

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$a Lotti Diaz, Leilani M $u Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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$a Border, Sarah E $u Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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$a Sojka, Daniel $u Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
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$a Fajtova, Pavla $u Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
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$a Salvesen, Guy S $u Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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