In a healthy eye, the proper homeostasis of vitamin A (all-trans-retinol, atROL) supports visual function under a variety of lighting conditions. However, certain environmental insults in combination with an unfavorable genetic background can overcome the adaptive capabilities of ocular retinoid metabolism and compromise retinal function. The clinical examples are Stargardt disease, an inherited form of juvenile macular degeneration and Age-related macular degeneration (AMD), in which an imbalance in retinoid metabolism is an important etiologic factor. Despite intensive studies, FDA approved treatments for inherited or acquired degenerative retinal diseases are very limited. In this project, we propose to expand potential treatment options for the retinal degenerative diseases by developing a safe and effective method of controlling the ocular flux of retinoids by targeting vitamin A binding proteins. To obtain insight into the potential therapeutic applications of this approach, we propose comprehensive studies that combine diverse biochemical, biophysical, and physiological methods aimed at developing candidate drugs and assessing their biological effects in animal models of human retinal degenerative diseases. To achieve these goals, we propose three specific aims.
In Aim 1, we will utilize high-throughput screening (HTS) technology to identify small-molecule antagonists of cellular retinol-binding protein (CRBP1). We will select lead compounds and characterize their binding properties. We will also validate their biological activity in a cell-based secondary assay. Ultimately, we will pre-select the first-in-class drug candidates that allow for the pharmaceutical manipulation of retinoid metabolism.
In Aim 2, the therapeutic potential of CRBP1 ligands will be assessed by evaluating changes in biochemical and pathophysiological processes in the retinas in vivo. The results of experimental therapies will be monitored by electroretinograms, non-invasive imaging techniques, including optical coherence tomography, scanning laser ophthalmoscopy, and two-photon microscopy, whereas ocular retinoid metabolism will be examined with advanced analytical tools. Ultimately, we will link the biochemical properties of CRBP1 antagonists with their therapeutic effects, and thus provide solid proof-of-concept data that could be further developed into initial clinical trials.
In Aim 3, we will combine the structural information about the mode of non-retinoid ligands interaction with CRBP1 and methods of medicinal chemistry to rationally improve pharmacodynamic properties of drug candidates. We will also determine pharmacokinetics of the selected drug candidates in the context of their ability to cross the blood/retina barrier. The completion of these experiments will identify the chemical properties that provide the best efficacy profile for the lead compounds. Together, our studies will contribute a novel mechanism-based therapeutic strategy for blinding eye conditions and first-in-class drug candidates pre-tested in vivo that will expand treatment options for millions of patients affected by retinal degenerative diseases.
Effective therapies for blinding retinal degenerative diseases are unmet medical needs. Retinaldehyde reactivity and the accumulation of its metabolites is an etiologic factor in retinal and macular degenerations of multiple causes. Thus, research towards the development of pharmacological approaches to influence retinoid metabolism promises new methods for the prevention of these ocular conditions. In this proposal, we validate cellular retinol-binding protein 1 as a relevant therapeutic target and identify a new class of drugs effective against progressive retinal degeneration.
| Chen, Yuanyuan; Chen, Yu; Jastrzebska, Beata et al. (2018) A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration. Nat Commun 9:1976 |
| Gao, Songqi; Parmar, Tanu; Palczewska, Grazyna et al. (2018) Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration. Mol Pharmacol 94:1132-1144 |
| Silvaroli, Josie A; Pleshinger, Matthew J; Banerjee, Surajit et al. (2017) Enzyme That Makes You Cry-Crystal Structure of Lachrymatory Factor Synthase from Allium cepa. ACS Chem Biol 12:2296-2304 |
| Arne, Jason M; Widjaja-Adhi, Made Airanthi K; Hughes, Taylor et al. (2017) Allosteric modulation of the substrate specificity of acyl-CoA wax alcohol acyltransferase 2. J Lipid Res 58:719-730 |
| Sundermeier, Thomas R; Sakami, Sanae; Sahu, Bhubanananda et al. (2017) MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice. J Biol Chem 292:3366-3378 |
| Widjaja-Adhi, Made Airanthi K; Palczewski, Grzegorz; Dale, Kali et al. (2017) Transcription factor ISX mediates the cross talk between diet and immunity. Proc Natl Acad Sci U S A 114:11530-11535 |
| Gorelenkova Miller, Olga; Cole, Kyle S; Emerson, Corey C et al. (2017) Novel chloroacetamido compound CWR-J02 is an anti-inflammatory glutaredoxin-1 inhibitor. PLoS One 12:e0187991 |
| Chelstowska, Sylwia; Widjaja-Adhi, Made Airanthi K; Silvaroli, Josie A et al. (2017) Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis. Biochemistry 56:4489-4499 |
| Babino, Darwin; Golczak, Marcin; Kiser, Philip D et al. (2016) The Biochemical Basis of Vitamin A3 Production in Arthropod Vision. ACS Chem Biol 11:1049-57 |
| Silvaroli, Josie A; Arne, Jason M; Chelstowska, Sylwia et al. (2016) Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures. J Biol Chem 291:8528-40 |
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