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

Guzelj, Samo (author), Jakopin, Žiga (author)

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.

• Language: English
• Keywords: NOD1 agonist, constrained meso-DAP mimetics, NOD1 activation, innate immune agonist, bioisosteric replacement, rigidization
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 13 str.
• Numbering: Vol. 25, iss. 22, art. 5228
• PID: 20.500.12556/RUL-134690
• UDC: 663.2:663.4:547.56:66.094.3.097.8
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules25225228
• COBISS.SI-ID: 36482307
• Publication date in RUL: 26.01.2022

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 10.11.2020

Secondary language

• Language: Slovenian
• Keywords: agonist prirojene imunosti, bioizosterna zamenjava, NOD1 agonisti, aktivacija NOD1, rigidizirani mimetiki mezo-DAP

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Project number: J3-9256
• Name: Razvoj agonistov receptorja NOD2 ter dualnih NOD2/TLR7 agonističnih konjugatov kot novih adjuvansov za cepiva