期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 209, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112863
关键词
Desmuramyl peptides; ICAM-1; Immunomodulatory agents; TNF-alpha; NOD2 ligands
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC) [EGP 469917-14, RGPIN 2017-05363]
NOD2 is a surveillance receptor of the immune system that recognizes bacterial and viral infections. By strategically re-designing molecules, the beneficial properties of MDP can be utilized for the rational design of new vaccine adjuvants. The novel DMPs trigger higher levels of TNF-alpha release, indicating potential immunomodulatory therapeutic benefits.
Nucleotide-binding oligomerization domain 2 (NOD2) is cytosolic surveillance receptor of the innate immune system capable of recognizing the bacterial and viral infections. Muramyl dipeptide (MDP) is the minimal immunoreactive unit of murein. NOD2 perceives MDP as pathogen-associated molecular pattern, thereby triggering an immune response with undesirable side-effects. Beneficial properties of MDP, such as pro-inflammatory characteristics for the rational design of new vaccine adjuvants, can be harnessed by strategically re-designing the molecule. In this work, a new class of amphiphilic desmur-amylpeptides (DMPs) were synthesized by replacing the carbohydrate moiety (muramic acid) of the parent molecule with hydrophilic arenes. A lipophilic chain was also introduced at the C-terminus of dipeptide moiety (alanine-isoglutamine), while conserving its L-D configuration. These novel DMPs were found to set off the release of higher levels of tumour necrosis factor alpha (TNF-alpha) than Murabutide, which is a well-known NOD2 agonist. Molecular docking studies indicate that all these DMPs bind well to NOD2 receptor with similar dock scores (binding energy) through a number of hydrogen bonding and hydrophobic/pi interactions with several crucial residues of the receptor. More studies are needed to further assess their immunomodulatory therapeutic potential, as well as the possible involvement of NOD2 activation. (c) 2020 Elsevier Masson SAS. All rights reserved.
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