Discovery of desmuramylpeptide NOD2 agonists with single-digit nanomolar potency

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

The innate immune receptor nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) represents an important target for the development of structurally defined small molecule immunomodulatory compounds that have great potential to be used either as vaccine adjuvants or as general immunostimulatory agents. We report here the investigation of the structure–activity relationship of a series of novel desmuramylpeptide NOD2 agonists. Extensive exploration of chemical space culminated in the discovery of a lipophilic adamantane-moiety-featuring compound 40, the first single-digit nanomolar and the most potent NOD2 agonist in its structural class to date. Moreover, 40 acted synergistically with lipopolysaccharide and interferon-γ to induce the production of cytokines in human peripheral blood mononuclear cells and enhance their nonspecific cytotoxic activity against K562 cancer cells. These findings provide initial insight into its immunostimulatory potential, especially when used in combination with other immunopotentiators.

• Language: English
• Keywords: NOD2, desmuramylpeptide, immunostimulant, adamantane, PBMC cytotoxicity, K562, agonists, cells, peptides and proteins, reaction products, toxicological synergy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: Str. 1270-1277
• Numbering: Vol. 13, iss. 8
• PID: 20.500.12556/RUL-140527
• UDC: 615.4:54:616-097
• ISSN on article: 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00121
• COBISS.SI-ID: 117643267
• Publication date in RUL: 15.09.2022

Record is a part of a journal

• Title: ACS medicinal chemistry letters
• Publisher: American Chemical Society
• ISSN: 1948-5875
• COBISS.SI-ID: 2959217

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.

Secondary language

• Language: Slovenian
• Keywords: farmacevtska kemija, imunomodulatorji, desmuramilpeptid, imunostimulanti, adamantan, PBMC citotoksičnost, K562, agonisti, celice, peptidi in proteini, reakcijski produkti, toksikološka sinergija