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: Tiratricol demonstrated moderate oral bioavailability (35%) in rats, with peak plasma concentrations (Cmax) of 8.2 μM achieved 2 hours after a 10 mg/kg dose [2].
- Plasma protein binding: High plasma protein binding (>95%) was observed in human serum albumin binding assays [2].
- Metabolism: Metabolized primarily in the liver via glucuronidation, with the major metabolite being Tiratricol glucuronide, which showed no antiviral activity [2].
Metabolism / Metabolites
Tiratricol is a metabolite of T4.

Toxicity Summary
Tiratricol is a naturally occurring metabolite of T4 (thyroxine) and a structural analog of T3 (triiodothyronine). Low concentrations of tiratricol are found in plasma, but tiratricol has no known role in thyroid physiology. Tiratricol has a high affinity for T3 receptors and suppresses thyroid stimulating hormone (TSH) secretion at therapeutic doses without causing significant peripheral effects, such as increased basal metabolism rate and heart rate. Tiratricol might lower total and LDL cholesterol, and stimulate bone formation. About 67% of an oral dose of tiratricol is absorbed; the half-life is 6 hours. (L2139) Serum sex hormone-binding globulin levels increased 55 +/- 13% with tiratricol, indicating an augmented hepatic response to tiratricol. Tiratricol had effected the cardiovascular function. Tiratricol has distinct augmented hepatic and skeletal thyromimetic actions of potential therapeutic value.

---

Health Effects
Orally, tiratricol can cause severe diarrhea, fatigue, lethargy, and profound weight loss. Heart attacks and strokes are possible, as well as symptoms of hyperthyroidism, including increased appetite, abdominal cramps, tremors, menstrual irregularities, nervousness, insomnia, sweating, intolerance to heat, fever, palpitations, tachycardia, increased pulse and blood pressure, chest pain, and cardiac arrhythmias. Case reports have implicated tiratricol in centrally-mediated hypothyroidism, pseudohypothyroidism, internuclear ophthalmoplegia, and hepatotoxicity. (L2139) It has been investigated for use in reducing goiter. It has also shown some effectiveness in reducing the atrophy caused when using corticosteroids. (Wikipedia) Tiratricol has been used to suppress pituitary TSH secretion, with reported attenuation of extrapituitary thyromimetic effects.

---

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

Tiratricol is a monocarboxylic acid that is (4-hydroxy-3,5-diiodophenyl)acetic acid in which the phenolic hydroxy group has been replaced by a 4-hydroxy-3-iodophenoxy group. It is a thyroid hormone analogue that has been used in the treatment of thyroid hormone resistance syndrome. It has a role as a thyroid hormone, an antiviral agent, an EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor, a nutraceutical, a human metabolite and an anti-obesity agent. It is an aromatic ether, a monocarboxylic acid, an organoiodine compound and a member of phenols.
A metabolite of T3 and T4 thyroid hormones; promoted for hyperlipidemia, localized lipodystrophy, and obesity. Tiratricol has been used in trials studying the treatment of Allan-Herndon-Dudley Syndrome.
Tiratricol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue. It is indicated in the management of thyroid hormone resistance syndrome and is used, in combination with levothyroxine, to suppress thyroid-stimulating hormone production in patients with thyroid cancer. It has been investigated for use in reducing goiter. It has also shown some effectiveness in reducing the atrophy caused when using corticosteroids. Tiratricol has also been widely marketed, under various trade names, as a weight loss aid. In 1999 and 2000, the United States Food and Drug Administration and Health Canada both issued warnings to the public regarding 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 prohibiting its sale.

---

Additional Info: - Mechanism of action: Tiratricol targets both viral polymerase and bacterial endotoxins through distinct binding modes, making it a dual-action therapeutic candidate for viral and bacterial infections [1, 2].
- FDA warning: The FDA has issued warnings against dietary supplements containing Tiratricol due to risks of thyrotoxicosis and cardiovascular complications [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.

---

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.

---

View More

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.

---

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