Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Their Common Age-Related Comorbidities

Cioffi, Christopher L.; Raja, Arun; Muthuraman, Parthasarathy; Jayaraman, Aravindan; Jayakumar, Srinivasan; Váradi, András; Rácz, Bóglárka; Petrukhin, Konstantin

doi:10.1021/acs.jmedchem.1c00099

Cited by 5 publications

(7 citation statements)

References 73 publications

(248 reference statements)

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“…Indirect strategies to target RBP4 are so-called ‘transthyretin tetramer kinetic stabilizers’. Instead of being ligands for RBP4, these small molecules bind TTR and stabilize its tetrameric assembly [ 193 ], thereby also lowering circulating RBP4 levels in mice. As these compounds prevent TTR aggregation in a gel-based assay in vitro, they might reduce the aggregation of unliganded TTR monomers in vivo, known to cause TTR amyloidosis and related comorbidities [ 193 ].…”

Section: Rbp4 As Therapeutic Target?mentioning

confidence: 99%

“…Instead of being ligands for RBP4, these small molecules bind TTR and stabilize its tetrameric assembly [ 193 ], thereby also lowering circulating RBP4 levels in mice. As these compounds prevent TTR aggregation in a gel-based assay in vitro, they might reduce the aggregation of unliganded TTR monomers in vivo, known to cause TTR amyloidosis and related comorbidities [ 193 ]. Of note, compounds that can bind both RBP4 and TTR bi-specifically have also been identified [ 194 ].…”

Section: Rbp4 As Therapeutic Target?mentioning

confidence: 99%

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Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

2022

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Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations.

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Section: Rbp4 As Therapeutic Target?mentioning

confidence: 99%

Section: Rbp4 As Therapeutic Target?mentioning

confidence: 99%

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

2022

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“… 10,27,28 Specifically, RNA silencers and gene editing tools are designed to act at the nucleic acid level to reduce TTR synthesis by the liver. Small molecule drugs are designed to act at the protein level to stabilize the TTR tetramer and limit the rate of dissociation to monomers and consequent amyloid formation 10,11,29 . Agents that disrupt pre‐existing amyloid fibrils promote their removal by macrophages 10 .…”

Section: Attr Treatment Strategiesmentioning

confidence: 99%

“…Small molecule drugs are designed to act at the protein level to stabilize the TTR tetramer and limit the rate of dissociation to monomers and consequent amyloid formation. 10,11,29 Agents that disrupt pre-existing amyloid fibrils promote their removal by macrophages. 10 The mechanism by which gene silencers reduce serum TTR and strategies to facilitate their selective delivery to hepatocytes are discussed below.…”

Section: Attr Treatment Strategiesmentioning

confidence: 99%

Liver‐directed drugs for transthyretin‐mediated amyloidosis

Brannagan

Berk²,

Gillmore

et al. 2022

J Peripheral Nervous Sys

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Transthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

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“…Retinol is water-insoluble and highly susceptible to oxidation, so RBP4 is crucial to its safe distribution to cells and tissues requiring it (Steinhoff et al, 2022). RBP4 is a relatively small protein (~21,000 Da) that would pass through the kidney glomerular filter and be lost to urine were it not in complex with transthyretin, the thyroxine transporter, resulting in a 1:1 stoichiometric complex of about 80 kDa in mass that is above the kidney threshold (Cioffi et al, 2021). The gradual rise in RBP4 levels in pups was mirrored by that of transthyretin (Figure S3).…”

Section: Vitamin and Hormone-binding Proteinsmentioning

confidence: 99%

Mirror image serum lipid carrier protein profiles in pup and lactating mother Atlantic grey seals reflect contrasting resource mobilisation challenges

McGill

Burchmore²,

Pomeroy³

et al. 2022

Front. Mar. Sci.

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True, phocid seals have the shortest known lactations relative to body mass, during which mass transfer of adipose stores from mother to offspring occurs at an unrivalled rate and extent. The mothers of most species of seal fast until weaning whilst their pups gorge on the most fat-rich milks known. This results in a dramatic reduction in maternal blubber mass while pups may triple their body weights before weaning. Mothers mobilise their blubber fat, transport it via blood to their mammary glands and into milk, whilst pups transfer fat in the opposite direction, from their intestines, via blood, to their blubber. Using proteomic analysis of mother and pup sera from Atlantic grey seals, we find that this mirror image flux of lipids between mothers and pups is reflected in an almost inverse relationship in the proteins in their blood specialised to transport fats, lipids, and fat-soluble vitamins. For instance, apolipoproteins ApoB-48/100, ApoA-II and ApoA-IV, which are structural components of the main lipid carrier complexes such as chylomicrons and HDL particles, occur at much higher levels in pups than mothers. Meanwhile, carriers of fat-soluble vitamins such as retinol- and vitamin D-binding proteins are lower in pups and gradually build towards weaning. In contrast, sex hormone-binding globulin occurs at remarkably high relative concentrations in pups. There are therefore dramatic differences between, and an unrealised complexity in, the balance of proteins involved in the rapid transfer of fats and other lipids from mother to pups in preparing their offspring for their post-weaning fasts on land and eventual survival at sea before they can feed again.

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Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Their Common Age-Related Comorbidities

Cited by 5 publications

References 73 publications

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

Liver‐directed drugs for transthyretin‐mediated amyloidosis

Mirror image serum lipid carrier protein profiles in pup and lactating mother Atlantic grey seals reflect contrasting resource mobilisation challenges

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