Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections
FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-biphenyl glycosides based on βGal and βGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc 69 with an IC50 of 0.19 μM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
---|---|
Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3668-3678 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Maddirala, Amarendar Reddy [VerfasserIn] |
---|
Links: |
---|
Themen: |
2L9GJK6MGN |
---|
Anmerkungen: |
Date Completed 15.03.2024 Date Revised 06.04.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1021/acs.jmedchem.3c02128 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM367981092 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM367981092 | ||
003 | DE-627 | ||
005 | 20240406232136.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240204s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1021/acs.jmedchem.3c02128 |2 doi | |
028 | 5 | 2 | |a pubmed24n1367.xml |
035 | |a (DE-627)NLM367981092 | ||
035 | |a (NLM)38308631 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Maddirala, Amarendar Reddy |e verfasserin |4 aut | |
245 | 1 | 0 | |a Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 15.03.2024 | ||
500 | |a Date Revised 06.04.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-biphenyl glycosides based on βGal and βGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc 69 with an IC50 of 0.19 μM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a diphenyl |2 NLM | |
650 | 7 | |a 2L9GJK6MGN |2 NLM | |
650 | 7 | |a Lectins |2 NLM | |
650 | 7 | |a Adhesins, Escherichia coli |2 NLM | |
650 | 7 | |a Biphenyl Compounds |2 NLM | |
700 | 1 | |a Tamadonfar, Kevin |e verfasserin |4 aut | |
700 | 1 | |a Pinkner, Jerome S |e verfasserin |4 aut | |
700 | 1 | |a Sanick, Denise |e verfasserin |4 aut | |
700 | 1 | |a Hultgren, Scott J |e verfasserin |4 aut | |
700 | 1 | |a Janetka, James W |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 5 vom: 14. März, Seite 3668-3678 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
773 | 1 | 8 | |g volume:67 |g year:2024 |g number:5 |g day:14 |g month:03 |g pages:3668-3678 |
856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.3c02128 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 67 |j 2024 |e 5 |b 14 |c 03 |h 3668-3678 |