Discovery of desmuramylpeptide NOD2 agonists with single-digit nanomolar potency

Guzelj, Samo (avtor), Bizjak, Špela (avtor), Jakopin, Žiga (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: NOD2, desmuramylpeptide, immunostimulant, adamantane, PBMC cytotoxicity, K562, agonists, cells, peptides and proteins, reaction products, toxicological synergy
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: Str. 1270-1277
• Številčenje: Vol. 13, iss. 8
• PID: 20.500.12556/RUL-140527
• UDK: 615.4:54:616-097
• ISSN pri članku: 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00121
• COBISS.SI-ID: 117643267
• Datum objave v RUL: 15.09.2022

Gradivo je del revije

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

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: farmacevtska kemija, imunomodulatorji, desmuramilpeptid, imunostimulanti, adamantan, PBMC citotoksičnost, K562, agonisti, celice, peptidi in proteini, reakcijski produkti, toksikološka sinergija