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Yong Li, Erning Xia, wang shen; The discovery of novel LFA-1 antagonist VVN001 to treat Dry Eye Disease (DED). Invest. Ophthalmol. Vis. Sci. 2019;60(9):293.
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© ARVO (1962-2015); The Authors (2016-present)
The research aims at discovering second generation cell adhesion molecule LFA-1 antagonist. The new LFA1 antagonist would have lower dosing frequency (patient compliance), less irritation upon instillation, and less other side effect such as dysgeusia (bad taste).
Structure-activity-relationship (SAR) studies were used to optimize a series phosphorus containing molecules into potent LFA-1 antagonists. Cellular assay of inhibition of Jurkat cell adhesion to ICAM-1 was used as the primary assay. Rabbit ocular pharmacokinetics, and mouse dry eye model are used to evaluate the molecules in vivo. Physicochemical properties and novel structures are also optimized during the process.
A highly potent, novel LFA-1 antagonist VVN001 is identified: Jurkat cell adhesion IC50 is < 10 nM.High concentration of the drug is found in cornea and conjunctiva tissues 24 hours after instillation of one drop 5% solution of drug to rabbit eyes. Specifically, >500 folds of IC50 in conjunctiva, and >100 folds of IC50 in cornea. These data indicate that once daily application of the new eye drop drug will be sufficient to treat dry eye disease.The novel new LFA-1 inhibitor also exhibits high water solubility (>10% aqueous solubility at pH 7.4), indicating potential less side when instilled into eyes.Mouse dry eye model indicates that the new novel LFA-1 antagonist VVN001 is more effective in treating dry eye disease than lifitegrast
A novel LFA-1 antagonist VVN001 is identified, which is potentially better than lifitegrast. The new drug VVN001 is currently under IND enabling studies, and is expected to enter clinical trials in late 2019.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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