Viral RNA-dependent RNA polymerase of NS5 (Yellow fever virus) (IC50: 0.754 ± 0.126 μM) [1]

- Antiviral activity: Tiratricol inhibited yellow fever virus (YFV) replication in Vero cells with an EC50 of 2.1 μM. Mechanistic studies showed direct binding to the viral NS5 RNA-dependent RNA polymerase, blocking viral RNA synthesis [1].
- Endotoxin neutralization: In LPS-stimulated RAW 264.7 macrophages, Tiratricol reduced TNF-α production by 65% at 20 μM. It directly bound to lipid A, the bioactive component of LPS, with an IC50 of 32 μM, preventing LPS-induced TLR4 activation [2].

- NS5 polymerase inhibition assay: Recombinant YFV NS5 polymerase was incubated with a fluorescent-labeled RNA template and nucleotides. Tiratricol dose-dependently inhibited polymerase activity, measured by fluorescence quenching. The IC50 was determined to be 0.754 ± 0.126 μM through kinetic analysis [1].
- LPS binding assay: A microplate-based assay using biotinylated LPS was performed. Tiratricol competed with LPS binding to immobilized anti-LPS antibodies, with an IC50 of 32 μM determined by colorimetric detection [2].

- Viral replication assay: Vero cells infected with YFV were treated with Tiratricol at concentrations ranging from 0.1 to 10 μM. Viral titers were measured by plaque assay, showing a dose-dependent reduction in viral yield with an EC50 of 2.1 μM [1].
- TNF-α inhibition assay: RAW 264.7 macrophages were pretreated with Tiratricol (1–50 μM) for 1 hour before LPS stimulation (1 μg/mL). TNF-α levels in supernatants were quantified by ELISA, revealing a 65% reduction at 20 μM [2].

Oral bioavailability: In rats, the oral bioavailability of telatreco is moderate (35%), with a peak plasma concentration (Cmax) of 8.2 μM 2 hours after administration of a 10 mg/kg dose [2]. Plasma protein binding: High plasma protein binding (>95%) was observed in the human serum albumin binding assay [2]. Metabolism: It is primarily metabolized in the liver via glucuronidation, with the major metabolite being telatreco glucuronide, which has not shown antiviral activity [2]. Metabolism/Metabolites: Telatreco is a metabolite of T4.

Toxicity Summary
Tilatrol is a natural metabolite of thyroxine (T4) and a structural analog of triiodothyronine (T3). Plasma concentrations of tilatrol are low, but it has no known role in thyroid physiology. Tilatrol has a high affinity for the T3 receptor and, at therapeutic doses, inhibits the secretion of thyroid-stimulating hormone (TSH) without causing significant peripheral effects such as increases in basal metabolic rate and heart rate. Tilatrol may lower total cholesterol and low-density lipoprotein cholesterol (LDL-C) and stimulate bone formation. Approximately 67% of orally administered tilatrol is absorbed; its half-life is 6 hours. (L2139) Following administration of tilatrol, serum sex hormone-binding globulin levels increased by 55 ± 13%, indicating an enhanced hepatic response to tilatrol. Tilatrol has cardiovascular effects. Tilatrol has a significant enhancing effect on hepatic and skeletal thyroid hormones, suggesting potential therapeutic value.

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Health Effects
Oral administration of telatrexol can cause severe diarrhea, fatigue, drowsiness, and significant weight loss. Heart attack and stroke may occur, as well as symptoms of hyperthyroidism, including increased appetite, abdominal cramps, tremors, menstrual irregularities, nervousness, insomnia, sweating, heat intolerance, fever, palpitations, tachycardia, increased pulse and blood pressure, chest pain, and arrhythmias. Case reports indicate that telatrexol is associated with central hypothyroidism, pseudohypothyroidism, internuclear ophthalmoplegia, and hepatotoxicity. (L2139) Telatrexol has been used to reduce goiter. It has also shown some efficacy in alleviating muscle atrophy caused by corticosteroid use. (Wikipedia) Telatrexol has been used to suppress pituitary thyroid-stimulating hormone (TSH) secretion and has been reported to attenuate extra-pituitar thyroid hormone-like effects.

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- Acute Toxicity: In mice, the oral LD50 was determined to be 450 mg/kg. No significant hepatotoxicity or nephrotoxicity was observed at therapeutic doses[2].
- Cardiovascular effects: High doses (≥50 mg/kg) caused tachycardia and increased blood pressure in rats, possibly due to activation of thyroid hormone receptors[2].

[1]. Tiratricol inhibits yellow fever virus replication through targeting viral RNA-dependent RNA polymerase of NS5. Antiviral Res. 2023 Nov;219:105737.

[2]. Tiratricol neutralizes bacterial endotoxins and reduces lipopolysaccharide-induced TNF-alpha production in the cell. Chem Biol Drug Des. 2008 Oct;72(4):320-8.

Tilatrexol is a monocarboxylic acid, namely (4-hydroxy-3,5-diiodophenyl)acetic acid, in which the phenolic hydroxyl group is replaced by 4-hydroxy-3-iodophenoxy. It is a thyroid hormone analogue that has been used to treat thyroid hormone resistance syndrome. It has multiple functions, including as a thyroid hormone, antiviral agent, EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor, nutritional supplement, human metabolite, and anti-obesity agent. It is an aromatic ether, monocarboxylic acid, organic iodine compound, and phenolic compound. It is a metabolite of T3 and T4 thyroid hormones and can be used to treat hyperlipidemia, localized lipodystrophy, and obesity. Tilatrexol was used in clinical trials to investigate the treatment of Allen-Herndon-Dudley syndrome. Tilatrexol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue. It is indicated for the treatment of thyroid hormone resistance syndrome and is used in combination with levothyroxine to suppress thyroid-stimulating hormone (TSH) secretion in patients with thyroid cancer. It has been used to shrink goiters. In addition, it has shown some efficacy in reducing atrophy caused by the use of corticosteroids. Tiratricol was also widely marketed under various brand names as a weight-loss adjunct. In 1999 and 2000, the U.S. Food and Drug Administration (FDA) and Health Canada issued warnings about the use of dietary supplements containing tiratricol. Tiratricol is not approved for sale in Canada or the United States. It was once an approved drug in Brazil, but its marketing authorization was suspended in 2003, effectively banning its sale.

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Additional information: - Mechanism of action: Tiratricol targets viral polymerases and bacterial endotoxins through different binding modes, making it a dual-activity candidate for the treatment of viral and bacterial infections [1, 2].
- FDA warning: The FDA has issued a warning regarding the risk of thyrotoxicosis and cardiovascular complications associated with dietary supplements containing Tiratricol [2].

C14H9I3O4

621.9354

621.763

51-24-1

1477-04-9 (hydrochloride salt)

5803

White to off-white solid powder

2.5±0.1 g/cm3

531.6±50.0 °C at 760 mmHg

181.5ºC

275.3±30.1 °C

0.0±1.5 mmHg at 25°C

1.767

5.47

2

4

4

21

356

0

C1=CC(=C(C=C1OC2=C(C=C(C=C2I)CC(=O)O)I)I)O

UOWZUVNAGUAEQC-UHFFFAOYSA-N

InChI=1S/C14H9I3O4/c15-9-6-8(1-2-12(9)18)21-14-10(16)3-7(4-11(14)17)5-13(19)20/h1-4,6,18H,5H2,(H,19,20)

2-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid

triiodothyroacetic acid; TRIAC; Tiratricol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 42 mg/mL (~67.53 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)