Chromenone derivatives as novel pharmacological chaperones for retinitis pigmentosa-linked rod opsin mutants.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
10 10 2022
10 10 2022
Historique:
received:
11
04
2022
revised:
23
05
2022
accepted:
24
05
2022
pubmed:
2
6
2022
medline:
15
10
2022
entrez:
1
6
2022
Statut:
ppublish
Résumé
The correct expression of folded, functional rhodopsin (Rho) is critical for visual perception. However, this seven-transmembrane helical G protein-coupled receptor is prone to mutations with pathological consequences of retinal degeneration in retinitis pigmentosa (RP) due to Rho misfolding. Pharmacological chaperones that stabilize the inherited Rho variants by assisting their folding and membrane targeting could slow the progression of RP. In this study, we employed virtual screening of synthetic compounds with a natural product scaffold in conjunction with in vitro and in vivo evaluations to discover a novel chromenone-containing small molecule with favorable pharmacological properties that stabilize rod opsin. This compound reversibly binds to unliganded bovine rod opsin with an EC50 value comparable to the 9-cis-retinal chromophore analog and partially rescued membrane trafficking of multiple RP-related rod opsin variants in vitro. Importantly, this novel ligand of rod opsin was effective in vivo in murine models, protecting photoreceptors from deterioration caused by either bright light or genetic insult. Together, our current study suggests potential broad therapeutic implications of the new chromenone-containing non-retinoid small molecule against retinal diseases associated with photoreceptor degeneration.
Identifiants
pubmed: 35642742
pii: 6596553
doi: 10.1093/hmg/ddac125
pmc: PMC9558842
doi:
Substances chimiques
Biological Products
0
Ligands
0
Receptors, G-Protein-Coupled
0
Rod Opsins
0
Rhodopsin
9009-81-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3439-3457Subventions
Organisme : NEI NIH HHS
ID : P30 EY011373
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY032874
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM129261
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM109825
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
J Biol Chem. 1995 Mar 10;270(10):5024-31
pubmed: 7890610
Pflugers Arch. 2021 Sep;473(9):1339-1359
pubmed: 33728518
Hum Mol Genet. 2014 Apr 1;23(7):1723-41
pubmed: 24214395
Molecules. 2018 Jan 27;23(2):
pubmed: 29382051
Nucleic Acids Res. 2017 Jun 20;45(11):e102
pubmed: 28335006
J Biol Chem. 2019 May 17;294(20):8101-8122
pubmed: 30944172
Mol Pharmacol. 2018 Oct;94(4):1132-1144
pubmed: 30018116
Neuropharmacology. 2009 Sep;57(4):438-45
pubmed: 19559036
J Clin Invest. 2013 Dec;123(12):5119-34
pubmed: 24231350
Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3224-30
pubmed: 18378578
Adv Exp Med Biol. 2014;801:471-6
pubmed: 24664733
Prog Retin Eye Res. 2018 Jan;62:1-23
pubmed: 29042326
Int J Mol Sci. 2019 Dec 10;20(24):
pubmed: 31835521
iScience. 2018 Jun 29;4:1-19
pubmed: 30240733
J Med Chem. 2013 Sep 12;56(17):7084-99
pubmed: 23888932
Eur J Med Chem. 2013 Jan;59:31-8
pubmed: 23202848
Arch Ophthalmol. 1993 Jun;111(6):761-72
pubmed: 8512476
ChemMedChem. 2018 Dec 6;13(23):2530-2545
pubmed: 30353976
Biochemistry. 2018 Sep 4;57(35):5188-5201
pubmed: 30085663
J Pharmacol Exp Ther. 2003 May;305(2):608-14
pubmed: 12606630
J Biol Chem. 2014 Mar 28;289(13):9288-303
pubmed: 24515108
J Neurosci. 2007 Aug 22;27(34):9043-53
pubmed: 17715341
J Biol Chem. 2006 Apr 28;281(17):11917-22
pubmed: 16495215
Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5247-52
pubmed: 22431612
Chem Biodivers. 2020 May;17(5):e1900746
pubmed: 32154628
Mol Neurobiol. 2015 Aug;52(1):679-95
pubmed: 25270370
Methods Enzymol. 1982;81:48-52
pubmed: 6212746
J Biol Chem. 2008 Sep 26;283(39):26684-93
pubmed: 18658157
Sci Rep. 2017 Mar 03;7:42717
pubmed: 28256516
J Neurosci Res. 2022 Apr;100(4):1063-1083
pubmed: 35165923
Adv Exp Med Biol. 2022;1371:61-77
pubmed: 34962636
Chem Rev. 2019 May 8;119(9):5537-5606
pubmed: 30608666
Sci Adv. 2020 Mar 04;6(10):eaay7505
pubmed: 32181350
Adv Exp Med Biol. 2010;664:317-23
pubmed: 20238031
Anal Biochem. 2016 Apr 15;499:63-65
pubmed: 26851339
J Biol Chem. 2004 Dec 24;279(52):54663-75
pubmed: 15489507
J Med Chem. 2016 Jul 28;59(14):6772-90
pubmed: 27396490
Molecules. 2020 Oct 23;25(21):
pubmed: 33114011
Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):3640-3645
pubmed: 29555765
J Biol Chem. 2011 Mar 25;286(12):10551-67
pubmed: 21224384
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11668-72
pubmed: 15277666
Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):E1428-37
pubmed: 24706832
Proc Natl Acad Sci U S A. 1983 Apr;80(7):1887-91
pubmed: 6572950
J Med Chem. 2013 Jun 27;56(12):5182-97
pubmed: 23713606
Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1327-34
pubmed: 19933196
Lancet. 2006 Nov 18;368(9549):1795-809
pubmed: 17113430
iScience. 2022 Mar 11;25(4):104060
pubmed: 35355518
Annu Rev Nutr. 2012 Aug 21;32:125-45
pubmed: 22809103
Respirology. 2001 Mar;6(1):15-21
pubmed: 11264758
J Comput Aided Mol Des. 2004 Mar;18(3):167-73
pubmed: 15368917
J Mol Biol. 2011 Jan 14;405(2):584-606
pubmed: 21094163
J Biol Chem. 2015 Feb 13;290(7):4304-18
pubmed: 25451936
Mol Pharmacol. 2021 Jan;99(1):60-77
pubmed: 33154094
J Biol Chem. 2022 Aug;298(8):102266
pubmed: 35850308
J Biol Chem. 2021 Dec;297(6):101359
pubmed: 34756884
J Biol Chem. 2003 Apr 18;278(16):14442-14450
pubmed: 12566452
Arch Ophthalmol. 1993 Jun;111(6):751-4
pubmed: 8512473
J Med Chem. 2017 Jan 12;60(1):362-372
pubmed: 27976894
J Biol Chem. 2004 Apr 16;279(16):16278-84
pubmed: 14769795
FASEB J. 2010 Sep;24(9):3196-209
pubmed: 20395457
Methods Mol Biol. 2015;1271:221-33
pubmed: 25697527
Nat Commun. 2018 May 17;9(1):1976
pubmed: 29773803
PLoS One. 2012;7(1):e30101
pubmed: 22276148