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M Elizabeth Fini, Jinhong Pan, Rafael Martínez-Carrasco, Steven Riesinger, Tsvetelina Lazarova; Structure-Activity Relationship (SAR) of Dynasore Analogues that Protect the Ocular Surface (OcS). Invest. Ophthalmol. Vis. Sci. 2020;61(7):3259.
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Dynasore is a cell-permeable small molecule inhibitor of dynamin-family GTPases and the endocytosis process, discovered after screening a library of 16,000 small chemical compounds against DNM1 GTPase activity (PMID:16740485). Recently, our lab reported that dynasore and the related compound dyngo 4a are remarkably protective of OcS epithelial cells and their mucosal glycocalyx, preventing damage caused by oxidative stress, thus precluding ocular surface barrier disruption (PMID:30303976). Here we describe our first results from a SAR study of dynasore-related compounds versus cytoprotection.
A SAR-by-purchase strategy was used to generate a small library of dynasore-related compounds. A cell culture model of human immortalized corneal limbal epithelial (HCLE) cells was used (PMID:12766048). Cultures were stressed by application of t-butyl hydroperoxide (3mM) for 2 hrs while also being treated with the compounds (at 10uM or 40uM). Cytoprotective activity was determined using the Calcein AM/CoCl2 assay(Thermo-Fisher).
After a substructure search in the SciFinder Database, 50 commercially-available compounds structurally-related to dynasore were selected for the initial SAR study. Several compounds showed cytoprotective activity, reaching around 60-80% of the activity of dynasore. After analysis of the initial data, some emerging SAR trends can be observed: most of the compounds which effectively inhibit oxidative damage contain branched alkyl groups on the carbon adjacent to the benzyl ring (509-1-1a, 509-1-3a and 509-1-7d). This may indicate a hydrophobic pocket in the binding site of the target protein, which the branched alkyl chain can access. Moreover, for the compounds where the naphthalene ring was replaced with a benzyl ring (509-1-1c, 509-1-5d, 509-1-7a, 509-1-7c and 509-1-9c), the activities are significantly decreased or showed no protection against oxidative stress. The compound 509-1-3a showed similar activity as dynasore.
Several compounds exhibiting cytoprotection were identified, validating the cell-based model and the SAR. The results are consistent with the conclusion that cytoprotection is mediated by targeting dynamin family GTPase(s) (PMID:24025110). Compound structure will be further optimized synthetically with the goal of therapeutic use for treating diseases of the OcS.
This is a 2020 ARVO Annual Meeting abstract.
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