Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma

Purkey, Hans E.; Dorrell, Michael I.

doi:10.1073/pnas.091431798

Cited by 108 publications

(169 citation statements)

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“…23 Flufenamic acid's plasma selectivity is also better than diflunisal's. 29 The shortcomings of flufenamic acid include its lower maximum therapeutic serum level (Table 2) and the fact that it is an approved drug only outside the United States.…”

Section: Discussionmentioning

confidence: 99%

“…23,24,26,27 The structures of the inhibitors utilized in this study, along with their corresponding dissociation constants, maximum therapeutic serum levels, and human plasma binding stoichiometries are summarized in Table 2. 23,[28][29][30] Diclofenac, diflunisal, and flufenamic acid are all nonsteroidal antiinflammatory drugs (NSAIDs). The first two are Food and Drug Administration (FDA) approved.…”

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confidence: 99%

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Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Miller

Sekijima

Kelly

2004

Laboratory Investigation

182

163

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Transthyretin (TTR) tetramer dissociation and misfolding affords a monomeric amyloidogenic intermediate that misassembles into aggregates including amyloid fibrils. Amyloidogenesis of wild-type (WT) TTR causes senile systemic amyloidosis (SSA), whereas fibril formation from one of the more than 80 TTR variants leads to familial amyloidosis, typically with earlier onset than SSA. Several nonsteroidal anti-inflammatory drugs (NSAIDs) stabilize the native tetramer, strongly inhibiting TTR amyloid fibril formation in vitro. Structure-based designed NSAID analogs are even more potent amyloid inhibitors. The effectiveness of several NSAIDs, including diclofenac, diflunisal, and flufenamic acid, as well as the diclofenac analog, 2-[(3,5-dichlorophenyl) amino] benzoic acid (inhibitor 1), has been demonstrated against WT TTR amyloidogenesis. Herein, the efficacy of these compounds at preventing acid-induced fibril formation and urea-induced tetramer dissociation of the most common disease-associated TTR variants (V30M, V122I, T60A, L58H, and I84S) was evaluated. Homotetramers of these variants were employed for the studies within, realizing that the tetramers in compound heterozygote patients are normally composed of a mixture of WT and variant subunits. The most common familial TTR variants were stabilized substantially by flufenamic acid and inhibitor 1, and to a lesser extent by diflunisal, against acid-mediated fibril formation and chaotrope denaturation, suggesting that this chemotherapeutic option is viable for patients with familial transthyretin amyloidosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Miller

Sekijima

Kelly

2004

Laboratory Investigation

182

163

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“…Antibodies, raised as described in ref. 53, were purified by passage of rabbit serum over a recombinant staphylococcal protein A column. The column was washed with 5 column volumes of 50 mM sodium phosphate buffer (pH 7.2), and the antibodies were eluted with 5 column volumes of 100 mM sodium citrate buffer (pH 3).…”

Section: Ttr Tetramer Dissociation Kinetics At Neutral Ph Followed Bymentioning

confidence: 99%

“…The concentrated protein (7 mg͞ ml) was then coupled to cyanogen bromide-activated Sepharose as described in ref. 53. The Sepharose gel (1 g of gel per 35 mg of protein) was first washed in a filter funnel with 1,400 ml of 1 mM HCl for 15 min.…”

Section: Ttr Tetramer Dissociation Kinetics At Neutral Ph Followed Bymentioning

confidence: 99%

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Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and -Amyloid in Normal Adults

Fishel¹

2005

Archives of Neurology

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Background: Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on ␤-amyloid (A␤). Hyperinsulinemia induces inflammation and is a risk factor for Alzheimer disease. Thus, insulin ab-normalitiesmaycontributetoAlzheimerdiseasepathophysiology through effects on the inflammatory network. Objectives:To determine the effects of induced hyperinsulinemia with euglycemia on A␤, transthyretin, and inflammatory markers and modulators in plasma and cerebrospinal fluid (CSF).Design: Randomized crossover trial. Setting: Veterans Affairs hospital clinical research unit.Participants: Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2 years).Interventions: On separate mornings, fasting participants received randomized infusions of saline or insulin (1.0 mU·kg -1 ·min -1 ) with variable dextrose levels to maintain euglycemia, achieving plasma insulin levels typical of insulin resistance. Plasma and CSF were collected after an approximately 105-minute infusion. Main Outcome Measures:Plasma and CSF levels of interleukin 1␣, interleukin 1␤, interleukin 6, tumor necrosis factor ␣, F 2 -isoprostane (CSF only), A␤, norepinephrine, transthyretin, and apolipoprotein E.Results: Insulin increased CSF levels of F 2 -isoprostane and cytokines (both PϽ.01), as well as plasma and CSF levels of A␤42 (both PϽ.05). The changes in CSF levels of A␤42 were predicted by increased F 2 -isoprostane and cytokine levels (both PϽ.01) and reduced transthyretin levels (P=.02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both PϽ.05).Conclusion: Moderate hyperinsulinemia can elevate inflammatory markers and A␤42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

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Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma

Cited by 108 publications

References 58 publications

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and -Amyloid in Normal Adults

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