Halofuginone - ITP 9% Increase in Mouse Lifespan (Males)

#1

Halofuginone is a synthetic, anti-parasitic drug, a derivative of the plant-derived alkaloid febrifugine, used in veterinary medicine to treat coccidiosis and cryptosporidiosis. It works by inhibiting prolyl-tRNA synthetase (ProRS), a crucial enzyme in protein synthesis. Beyond its antiparasitic use, halofuginone has demonstrated potential as a treatment for fibrosis, cancer, and autoimmune disorders by inhibiting collagen synthesis and angiogenesis, as well as by modulating the TGF-β signaling pathway.

Uses

  • Veterinary Medicine:

Halofuginone is used as a coccidiostat and in the treatment of parasitic infections in animals, such as cryptosporidiosis in calves.

  • Human Medicine (Investigational):

It is being investigated for its potential to treat various human diseases, including:

  • Cancer: By inhibiting tumor progression and metastasis.
  • Fibrosis: By suppressing collagen synthesis and fibroblast activation.
  • Autoimmune Disorders: By modulating immune cell differentiation.
  • Obesity: By influencing metabolic pathways and hormone levels.

Mechanism of Action

Halofuginone has a multifaceted mechanism of action:

Halofuginone inhibits ProRS, a key enzyme in protein synthesis, which is vital for combating parasitic infections like malaria and cryptosporidiosis.

  • Inhibition of Fibrosis and Angiogenesis:

It inhibits the expression of collagen type I and Matrix Metalloproteinase 2 (MMP-2), and suppresses the TGF-β/Smad3 signaling pathway, which is involved in fibrosis and tumor metastasis.

  • Immune Modulation:

It can inhibit the differentiation of pro-inflammatory Th17 cells and modulate amino acid starvation responses, suggesting potential benefits for autoimmune disorders.

Origin

  • Natural Source:

Halofuginone is a synthetic derivative of febrifugine, a quinazolinone alkaloid found in the Chinese herb Dichroa febrifuga, which has been used in traditional Chinese medicine for centuries.

  • Synthesis:

Halofuginone was synthesized to reduce the toxicity associated with the natural febrifugine, making it suitable for therapeutic use in animals and human clinical trials.

#2

The primary side effects of halofuginone in humans are nausea, vomiting, fatigue, and in some cases, bleeding complications. Other reported adverse events include diarrhea, constipation, anorexia, and liver toxicity. Due to these side effects, particularly the potential for liver toxicity, halofuginone has not translated into a widely used clinical medicine.

Common Side Effects

  • Gastrointestinal issues: Nausea and vomiting are frequently reported.
  • General fatigue: Patients may experience a general feeling of tiredness.
  • Bleeding complications: Some patients have experienced bleeding problems.
  • Digestive issues: Diarrhea and constipation have also been observed.

Other Reported Effects

  • Anorexia: A loss of appetite has been noted.
  • Liver toxicity: Halofuginone can cause damage to the liver.
  • Dehydration and prostration: These effects have been linked to higher doses of the drug.

Why Halofuginone is not widely used

  • Promising activity but significant side effects:

While halofuginone has shown promising biological activity, its side effect profile has limited its clinical application.

  • Limited therapeutic use:

Despite being studied, it has not been developed into a commonly used therapeutic drug for humans.

In summary: While halofuginone shows potential in certain research areas, its side effects, especially nausea, vomiting, fatigue, and potential liver toxicity, have restricted its use as a human medicine.

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#3

Based on the potential side effects and a quick dive into this drug, I think I’ll skip this one. Unless there is something I’m missing.

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#4

Interesting! Halofuginone inhibits protein synthesis, a little bit like rapamycin perhaps.

It is not available for purchase in India, from what I can see.

Is halofuginone FDA approved?

Halofuginone, a synthetic derivative of a plant-alkaloid febrifugine, has shown anti-fibrotic and type I collagen synthesis inhibitory activities (McGaha et al., 2002). It has been granted approval by FDA for the treatment of scleroderma.

What is the mechanism of action of halofuginone?

AI Overview

Halofuginone works by inhibiting prolyl-tRNA synthetase (ProRS). This enzyme is crucial for protein synthesis, as it “charges” prolyl-tRNA with proline, making it ready for protein production. By inhibiting this process, halofuginone causes an accumulation of uncharged tRNAs, mimicking an amino acid starvation response. This response leads to various effects, including the suppression of pro-inflammatory T helper 17 (Th17) cells, a reduction in collagen production and fibrosis, and inhibition of tumor growth.

More info:

Detailed Mechanism of Action

    1. Enzyme inhibition:

Halofuginone binds to the active site of prolyl-tRNA synthetase (ProRS), a component of the glutamyl-prolyl-tRNA synthetase (EPRS) complex.

    1. ATP-dependent binding:

This binding is ATP-dependent, with halofuginone occupying the positions of both the bound proline and the 3’ end of the tRNA.

    1. Prolyl-tRNA charging blockage:

By blocking ProRS, halofuginone prevents the charging of tRNA with proline, a process essential for the incorporation of proline into proteins.

    1. Amino acid starvation response (AAR):

The accumulation of uncharged tRNAs triggers the cell’s amino acid starvation response (AAR).

    1. Therapeutic effects:

The AAR pathway activation has several downstream consequences, including:

  • Immunomodulation: Selectively inhibits the differentiation of pro-inflammatory Th17 cells, which are involved in autoimmune diseases.
  • Anti-fibrotic effects: Reduces the synthesis of collagen and extracellular matrix proteins, inhibiting fibrosis.
  • Anti-tumor effects: Suppresses collagen type I expression and other factors that support tumor growth and invasiveness.
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Anti-Aging Drugs and Aging Rate Indicators | Richard A. Miller (Halofuginone and MSDC-160 9% males)