Samo Guzelj (Author), Žiga Jakopin (Author)

Abstract

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 [alpha]-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.

Keywords

NOD1 agonist;constrained meso-DAP mimetics;NOD1 activation;innate immune agonist;bioisosteric replacement;rigidization;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 663.2:663.4:547.56:66.094.3.097.8
COBISS: 36482307 Link will open in a new window
ISSN: 1420-3049
Views: 105
Downloads: 102
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Other data

Secondary language: Slovenian
Secondary keywords: agonist prirojene imunosti;bioizosterna zamenjava;NOD1 agonisti;aktivacija NOD1;rigidizirani mimetiki mezo-DAP;
Type (COBISS): Article
Pages: str. 1-13
Volume: ǂVol. ǂ25
Issue: ǂno. ǂ22
Chronology: 2020
DOI: 10.3390/molecules25225228
ID: 14363906