Assay of Retinol-Binding Protein–Transthyretin Interaction and Techniques to Identify Competing Ligands

Mata, Nathan L.; Phan, Kim B.; Han, Yun

doi:10.1007/978-1-60327-325-1_12

Cited by 3 publications

(3 citation statements)

References 22 publications

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“…It was shown to induce the disruption of the tertiary retinol-RBP4-TTR complex in circulation, with subsequent lowering in serum RBP4 and retinol levels. 11,44 Additionally, it was proven experimentally that fenretinide-induced serum retinol lowering is associated with partial depletion of visual cycle retinoids and accompanied by significant reduction of bisretinoid production in the Abca4 À/À model. 11 As fenretinide safety profile may be incompatible with chronic dosing in individuals with atrophic AMD and Stargardt disease, identification of new structural classes of RBP4 antagonists is highly important.…”

Section: Discussionmentioning

confidence: 99%

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

Dobri¹,

Qin²,

Kong³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

122

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PURPOSE. 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 RARa 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 Abca4À/À 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 RARa agonist indicating a more favorable safety profile for this nonretinoid compound. (Invest Ophthalmol Vis Sci. 2013; 54:85-95)

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Section: Discussionmentioning

confidence: 99%

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

Dobri¹,

Qin²,

Kong³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

122

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“…59 Retinol binds aRBP with a 1:1 stoichiometry and an affinity of 50–80 nM. 60 RBP samples were filtered (0.22 μ m) before being used. All retinol-containing samples were shielded from light, and fresh batches were regularly produced to minimize retinol oxidation.…”

Section: Methodsmentioning

confidence: 99%

“…The A 330 / A 280 ratio of hRBP was approximately 0.80, which corresponds to 85% saturation of RBP with retinol . Retinol binds aRBP with a 1:1 stoichiometry and an affinity of 50–80 nM . RBP samples were filtered (0.22 μm) before being used.…”

Section: Materials and Methodsmentioning

confidence: 99%

Retinol-Binding Protein Interferes with Transthyretin-Mediated β-Amyloid Aggregation Inhibition

Mangrolia

Murphy

2018

Biochemistry

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β-Amyloid (Aβ) aggregation is causally linked to Alzheimer's disease. On the basis of in vitro and transgenic animal studies, transthyretin (TTR) is hypothesized to provide neuroprotection against Aβ toxicity by binding to Aβ and inhibiting its aggregation. TTR is a homotetrameric protein that circulates in blood and cerebrospinal fluid; its normal physiological role is as a carrier for thyroxine and retinol-binding protein (RBP). RBP forms a complex with retinol, and the holoprotein (hRBP) binds with high affinity to TTR. In this study, the role of TTR ligands in TTR-mediated inhibition of Aβ aggregation was investigated. hRBP strongly reduced the ability of TTR to inhibit Aβ aggregation. The effect was not due to competition between Aβ and hRBP for binding to TTR, as Aβ bound equally well to TTR-hRBP complexes and TTR. hRBP is known to stabilize the TTR tetrameric structure. We show that Aβ partially destabilizes TTR and that hRBP counteracts this destabilization. Taken together, our results support a mechanism wherein TTR-mediated inhibition of Aβ aggregation requires not only TTR-Aβ binding but also destabilization of TTR quaternary structure.

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Alexa Fluor 430 carboxylic acid succinimidyl ester

Sabnis¹

2015

Handbook of Fluorescent Dyes and Probes

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Assay of Retinol-Binding Protein–Transthyretin Interaction and Techniques to Identify Competing Ligands

Cited by 3 publications

References 22 publications

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

Retinol-Binding Protein Interferes with Transthyretin-Mediated β-Amyloid Aggregation Inhibition

Alexa Fluor 430 carboxylic acid succinimidyl ester

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