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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 modifica...

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Autores principales: Guzelj, Samo, Jakopin, Žiga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698283/
https://www.ncbi.nlm.nih.gov/pubmed/33182604
http://dx.doi.org/10.3390/molecules25225228
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author Guzelj, Samo
Jakopin, Žiga
author_facet Guzelj, Samo
Jakopin, Žiga
author_sort Guzelj, Samo
collection PubMed
description 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.
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spelling pubmed-76982832020-11-29 Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists Guzelj, Samo Jakopin, Žiga Molecules Article 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. MDPI 2020-11-10 /pmc/articles/PMC7698283/ /pubmed/33182604 http://dx.doi.org/10.3390/molecules25225228 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guzelj, Samo
Jakopin, Žiga
Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title_full Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title_fullStr Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title_full_unstemmed Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title_short Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists
title_sort synthesis of conformationally constrained d-glu-meso-dap analogs as innate immune agonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698283/
https://www.ncbi.nlm.nih.gov/pubmed/33182604
http://dx.doi.org/10.3390/molecules25225228
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