Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts

Investigative Ophthalmology & Visual Science
Kathleen S MolnarUsha P Andley

Abstract

We previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity. We compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy. Docking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-...Continue Reading

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Citations

Jun 20, 2020·Journal of Neuroinflammation·Man Ying WongWenjie Luo
Jun 3, 2020·Journal of Medicinal Chemistry·Kuei-Ju ChengJing-Ping Liou
Dec 10, 2021·Investigative Ophthalmology & Visual Science·Sheldon RowanAllen Taylor

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Methods Mentioned

BETA
thermal shift
nuclear magnetic resonance
size-exclusion chromatography
PCR
genotyping
light scattering
electron microscopy
NMR

Software Mentioned

GraphPad
Delphi
Topaz Moment
Topaz
Chimera
Prism
qnifft
cryAB
NanoTemper
Image Capture Engine

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