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Structure-guided design of D-galactal derivatives with high affinity and selectivity for the galectin-8 n-terminal domain
ID
Hassan, Mujtaba
(
Avtor
),
ID
Baussière, Floriane
(
Avtor
),
ID
Guzelj, Samo
(
Avtor
),
ID
Sundin, Anders
(
Avtor
),
ID
Håkansson, Maria
(
Avtor
),
ID
Kovačič, Rebeka
(
Avtor
),
ID
Leffler, Hakon
(
Avtor
),
ID
Tomašič, Tihomir
(
Avtor
),
ID
Anderluh, Marko
(
Avtor
),
ID
Jakopin, Žiga
(
Avtor
)
PDF - Predstavitvena datoteka,
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(3,43 MB)
MD5: A7FECB868FDE3A6634A30AF7768FC50F
URL - Izvorni URL, za dostop obiščite
https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.1c00371
Galerija slik
Izvleček
Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.
Jezik:
Angleški jezik
Ključne besede:
Galectin-8N
,
d-galactal
,
benzimidazole
,
selectivity
,
X-ray crystallography
,
cytokine secretion
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:
2021
Št. strani:
Str. 1745-1752
Številčenje:
Vol. 12, iss. 11
PID:
20.500.12556/RUL-141454
UDK:
615.4:54:616-006
ISSN pri članku:
1948-5875
DOI:
10.1021/acsmedchemlett.1c00371
COBISS.SI-ID:
83202819
Datum objave v RUL:
29.09.2022
Število ogledov:
481
Število prenosov:
67
Metapodatki:
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Objavi na:
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.
Projekti
Financer:
Drugi - Drug financer ali več financerjev
Program financ.:
Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement
Številka projekta:
765581
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