title: A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis.
abstract: OBJECTIVE
  Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120.
  
  
  METHODS
  RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques.
  
  
  RESULTS
  In comparison to fenretinide, A1120 did not act as a RARα agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation.
  
  
  CONCLUSIONS
  A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4(-/-) animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120. In contrast to fenretinide, A1120 does not act as a RARα agonist indicating a more favorable safety profile for this nonretinoid compound.
authors.affiliation: Department of Ophthalmology, Columbia University, New York, New York 10032, USA.
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Dobri
authors.forename: Qiong
authors.initials: Q
authors.lastname: Qin
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Janet R
authors.initials: JR
authors.lastname: Sparrow
authors.forename: Konstantin
authors.initials: K
authors.lastname: Petrukhin
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D004195:Disease Models, Animal; D017313:Fenretinide / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008024:Ligands; D008062:Lipofuscin / Q000378:metabolism*; D008268:Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011228:Prealbumin / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C540529:A1120 agent; D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D000970:Antineoplastic Agents; D008024:Ligands; D008062:Lipofuscin; D010880:Piperidines; D011228:Prealbumin; C101326:RBP4 protein, human; C502487:Rbp4 protein, mouse; D012176:Retinoids; D054839:Retinol-Binding Proteins, Plasma; D017313:Fenretinide; D006867:Hydrolases