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Fragment-sized and bidentate (immuno)proteasome inhibitors derived from cysteine and threonine targeting warheads
ID Kollár, Levente (Avtor), ID Gobec, Martina (Avtor), ID Proj, Matic (Avtor), ID Smrdel, Lara (Avtor), ID Knez, Damijan (Avtor), ID Gobec, Stanislav (Avtor), ID Sosič, Izidor (Avtor), ID Keserü M., György (Avtor), et al.

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Izvleček
Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC$_{50}$ values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

Jezik:Angleški jezik
Ključne besede:immunoproteasome, benzoxazole-2-carbonitriles, bidentate covalent inhibitors, fragments, non-covalent recognition
Vrsta gradiva:Članek v reviji
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Status publikacije:Objavljeno
Različica publikacije:Objavljena publikacija
Leto izida:2021
Št. strani:19 str.
Številčenje:Vol. 10, iss. 12, art. 3431
PID:20.500.12556/RUL-136689 Povezava se odpre v novem oknu
UDK:615.4:54
ISSN pri članku:2073-4409
DOI:10.3390/cells10123431 Povezava se odpre v novem oknu
COBISS.SI-ID:88025091 Povezava se odpre v novem oknu
Datum objave v RUL:16.05.2022
Število ogledov:474
Število prenosov:76
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
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Gradivo je del revije

Naslov:Cells
Skrajšan naslov:Cells
Založnik:MDPI
ISSN:2073-4409
COBISS.SI-ID:519958809 Povezava se odpre v novem oknu

Licence

Licenca:CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
Povezava:http://creativecommons.org/licenses/by/4.0/deed.sl
Opis:To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
Začetek licenciranja:06.12.2021

Sekundarni jezik

Jezik:Slovenski jezik
Ključne besede:farmacevtska kemija

Projekti

Financer:Drugi - Drug financer ali več financerjev
Program financ.:National Research Development and Innovation Office
Številka projekta:SNN_17 125496

Financer:Drugi - Drug financer ali več financerjev
Program financ.:National Research Development and Innovation Office
Številka projekta:2018-2.1.11-TÉT-SI-2018-00005

Financer:Drugi - Drug financer ali več financerjev
Program financ.:National Research Development and Innovation Office
Številka projekta:PD124598

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:P1-0208
Naslov:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:N1-0068
Naslov:Identifikacija nepeptidnih inhibitorjev imunoproteasoma z metodami razvoja učinkovin na osnovi fragmentov

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J3-1745
Naslov:Vloga imunoproteasoma v oblikovanju imunskega odziva, posredovanega s trombociti

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:Z1-1859
Naslov:Kovalentni zaviralci: zaviranje monoamin oksidaze preko nekatalitskih aminokislinskih ostankov

Financer:Drugi - Drug financer ali več financerjev
Program financ.:Gedeon Richter Talentum Foundation

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