TY - JOUR
T1 - Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics
AU - Li, Hao
AU - Illés, Peter
AU - Karunaratne, Chamini V.
AU - Nordstrøm, Lars Ulrik
AU - Luo, Xiaoping
AU - Yang, Annie
AU - Qiu, Yunping
AU - Kurland, Irwin J.
AU - Lukin, Dana J.
AU - Chen, Weijie
AU - Jiskrová, Eva
AU - Krasulová, Kristýna
AU - Pečinková, Petra
AU - DesMarais, Vera M.
AU - Liu, Qiang
AU - Albanese, Joseph M.
AU - Akki, Ashwin
AU - Longo, Michael
AU - Coffin, Breyen
AU - Dou, Vivi
AU - Mani, Sridhar
AU - Dvořák, Zdeněk
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/4
Y1 - 2021/4
N2 - Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure–activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure–activity relationships (SAR) between indole mimics and receptors, PXR and AhR.
AB - Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure–activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure–activity relationships (SAR) between indole mimics and receptors, PXR and AhR.
KW - Intestinal inflammation
KW - Microbial mimics
KW - Pregnane X receptor
KW - Tryptophan catabolites
UR - http://www.scopus.com/inward/record.url?scp=85101412725&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101412725&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2021.104661
DO - 10.1016/j.bioorg.2021.104661
M3 - Article
C2 - 33636438
AN - SCOPUS:85101412725
SN - 0045-2068
VL - 109
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 104661
ER -