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Discovery of desmuramylpeptide NOD2 agonists with single-digit nanomolar potency
ID
Guzelj, Samo
(
Author
),
ID
Bizjak, Špela
(
Author
),
ID
Jakopin, Žiga
(
Author
)
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MD5: 04B69478D2BC4FCDB21BB0EE3608F637
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https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00121
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Abstract
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
Views:
681
Downloads:
131
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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
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0420
Name:
Napredna imunološka zdravila in celični pristopi v farmaciji
Funder:
ARRS - Slovenian Research Agency
Project number:
J3-9256
Name:
Razvoj agonistov receptorja NOD2 ter dualnih NOD2/TLR7 agonističnih konjugatov kot novih adjuvansov za cepiva
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