title: Expansion of first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration.
abstract: All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: Jianye
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: Sreenivasa Reddy
authors.initials: SR
authors.lastname: Mundla
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: X Eric
authors.initials: XE
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: William
authors.initials: W
authors.lastname: Seibel
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.).
authors.forename: Ruben
authors.initials: R
authors.lastname: Papoian
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.) kxp65@case.edu mxg149@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (J.Z., Z.D., K.P., M.G.); Sreeni Laboratories Private Limited, Telangana, India (S.R.M.); Aroz Technologies LLC, Cincinnati, Ohio (X.E.H.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (W.S., R.P.) kxp65@case.edu mxg149@case.edu.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
mesh_terms: D000818:Animals; D002417:Cattle; D004224:Diterpenes / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010775:Photic Stimulation / Q000009:adverse effects*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D012172:Retinaldehyde / Q000378:metabolism*
chemical_list: D004224:Diterpenes; C009167:retinylamine; D012172:Retinaldehyde