20.500.12556/RUL-134690 Synthesis of conformationally constrained D-Glu-meso-DAP analogs as innate immune agonists 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. NOD1 agonist constrained meso-DAP mimetics NOD1 activation innate immune agonist bioisosteric replacement rigidization agonist prirojene imunosti bioizosterna zamenjava NOD1 agonisti aktivacija NOD1 rigidizirani mimetiki mezo-DAP true false true Angleški jezik Slovenski jezik Članek v reviji 2022-01-26 12:52:11 2022-01-26 12:52:15 2022-09-13 03:56:34 0000-00-00 00:00:00 2020 0 0 13 str. iss. 22, art. 5228 Vol. 25 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 663.2:663.4:547.56:66.094.3.097.8 1420-3049 10.3390/molecules25225228 36482307 RAZ_Guzelj_Samo_2020.pdf RAZ_Guzelj_Samo_2020.pdf 1 CD61878330E2605F69E7C51A7AA198A2 96843f880538da7fe951c7b31c152d666fddaa3344d107d263e605916b463d47 7f20c867-7e9e-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153263 https://www.mdpi.com/1420-3049/25/22/5228 1 33d8d11c-7e9e-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=153262 Fakulteta za farmacijo 0 0 0