Synthesis of conformationally constrained D-Glu-meso-DAP analogs as innate immune agonists

Guzelj, Samo (avtor), Jakopin, Žiga (avtor)

The dipeptide D-Glu-meso-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The meso-diaminopimelic acid (meso-DAP) moiety is known to be very stringent in terms of the allowed structural modifications which still retain the NOD1 activity. The aim of our study was to further explore the chemical space around the meso-DAP portion and provide a deeper understanding of the structural features required for NOD1 agonism. In order to achieve the rigidization of the terminal amine functionality of meso-DAP, isoxazoline and pyridine heterocycles were introduced into its side-chain. Further, we incorporated the obtained meso-DAP mimetics into the structure of iE-DAP. Collectively, nine innovative iE-DAP derivatives additionally equipped with lauroyl or didodecyl moieties at the α-amino group of D-Glu have been prepared and examined for their NOD1 activating capacity. Overall, the results obtained indicate that constraining the terminal amino group of meso-DAP abrogates the compounds ability to activate NOD1, since only compound 6b retained noteworthy NOD1 agonistic activity, and underpin the stringent nature of this amino acid with regard to the allowed structural modifications.

• Jezik: Angleški jezik
• Ključne besede: NOD1 agonist, constrained meso-DAP mimetics, NOD1 activation, innate immune agonist, bioisosteric replacement, rigidization
• 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: 2020
• Št. strani: 13 str.
• Številčenje: Vol. 25, iss. 22, art. 5228
• PID: 20.500.12556/RUL-134690
• UDK: 663.2:663.4:547.56:66.094.3.097.8
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules25225228
• COBISS.SI-ID: 36482307
• Datum objave v RUL: 26.01.2022

Gradivo je del revije

• Naslov: Molecules
• Skrajšan naslov: Molecules
• Založnik: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

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: 10.11.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: agonist prirojene imunosti, bioizosterna zamenjava, NOD1 agonisti, aktivacija NOD1, rigidizirani mimetiki mezo-DAP

Projekti

• 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: J3-9256
• Naslov: Razvoj agonistov receptorja NOD2 ter dualnih NOD2/TLR7 agonističnih konjugatov kot novih adjuvansov za cepiva