Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F20%3A00537297" target="_blank" >RIV/60077344:_____/20:00537297 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.tandfonline.com/doi/pdf/10.1080/14756366.2020.1781107?needAcces" target="_blank" >https://www.tandfonline.com/doi/pdf/10.1080/14756366.2020.1781107?needAcces</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1080/14756366.2020.1781107" target="_blank" >10.1080/14756366.2020.1781107</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

Popis výsledku v původním jazyce

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 and6, and aza-Asn derivatives that inhibitedS. mansoniandI. ricinuslegumains. 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 initialin vitroselectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

Název v anglickém jazyce

Design, synthesis, andin vitroevaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

Popis výsledku anglicky

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 and6, and aza-Asn derivatives that inhibitedS. mansoniandI. ricinuslegumains. 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 initialin vitroselectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/EF16_019%2F0000759" target="_blank" >EF16_019/0000759: Centrum výzkumu patogenity a virulence parazitů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Enzyme Inhibition and Medicinal Chemistry

ISSN

1475-6366

e-ISSN

—

Svazek periodika

35

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

17

Strana od-do

1387-1402

Kód UT WoS článku

000547415900001

EID výsledku v databázi Scopus

2-s2.0-85087609330