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

Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3320-3331. doi: 10.1167/iovs.18-25647.


Purpose: 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.

Methods: 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.

Results: 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-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.

Conclusions: The ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Ophthalmic
  • Animals
  • Cataract / drug therapy*
  • Cataract / metabolism
  • Cataract / pathology
  • Chromatography, Gel
  • Disease Models, Animal
  • Fluorometry
  • Lens, Crystalline / drug effects
  • Lens, Crystalline / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Ophthalmic Solutions
  • Oxysterols / metabolism
  • Oxysterols / pharmacology*
  • Protein Aggregation, Pathological / drug therapy
  • Slit Lamp
  • alpha-Crystallin B Chain / metabolism*


  • Ophthalmic Solutions
  • Oxysterols
  • alpha-Crystallin B Chain

Supplementary concepts

  • Cataract, Age-Related Nuclear