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Key Differences Between ATH434 and Deferiprone

1. Mechanism of Action in Iron Regulation

• The article highlights important differences in the mechanisms of action between ATH434 and deferiprone.
• ATH434 is designed to address diseases driven by iron-induced oxidative damage.

2. Fe²⁺ as a Catalyst of Oxidative Stress

• The form of iron that catalyzes oxidative stress, as depicted in Figure 2, is Fe²⁺.
• Our recent publication (Pall et al., 2024) confirms that ATH434 has an affinity for Fe²⁺ similar to endogenous cellular Fe²⁺ chaperones (e.g., glutathione, poly-C-binding proteins).
• These proteins regulate Fe²⁺ by:
  • Supplying Fe²⁺ to enzymes.
  • Shuttling Fe²⁺ into safe storage.
  • Facilitating normal iron export.
• By enhancing the buffering capacity of these proteins, ATH434 helps limit Fe²⁺'s ability to trigger oxidative stress.

3. Deferiprone's Interaction with Fe²⁺ and Fe³⁺

• Under normal cellular conditions, deferiprone is unlikely to bind Fe²⁺ in a meaningful way.

• Deferiprone has a much higher affinity for Fe³⁺ than Fe²⁺.

• Before deferiprone can "trap" or bind Fe²⁺, an electron is ejected from the Fe²⁺ complex, leading to two key consequences:

  a. Conversion of Fe²⁺ to Fe³⁺

  • Table 1 in the article lists deferiprone as showing positive results in Friedreich’s ataxia (Pandolfo, ref 63).
  • However, Pandolfo (2013) notes that in a six-month trial, high doses of deferiprone worsened ataxia—similar to symptom worsening in Parkinson’s disease (PD) patients (Devos 2024, ref 55).
  • In Friedreich’s ataxia, neurons responsible for motor control are already starved of Fe²⁺; converting it to Fe³⁺ accelerates disease progression.
  • Similarly, in PD, neuromelanin helps aged primate brains sequester Fe²⁺.
  • However, Fe³⁺ must be converted back to Fe²⁺ for dopamine synthesis, which is critical for motor control.
  • In Devos (2024), hormonal biomarker data showed that deferiprone depleted central dopamine in a way that correlated with worsened motor function.
  • Deferiprone’s adverse effect on endogenous dopamine likely reflects unnecessary Fe³⁺ removal from dopamine-synthesizing enzymes, partly due to Fe²⁺ oxidation.

  b. Generation of Free Radicals

  • The ejected electron from Fe²⁺ oxidation contributes to oxidative stress.
  • This free electron reacts with oxygen, forming hydroxyl radicals (as discussed in Figure 1 of the article).
  • Free radicals damage intracellular structures, including DNA and lipids, leading to cellular injury.

How ATH434 Differs from Deferiprone

1. ATH434 Is Not an Iron Chelator

• ATH434 has a much weaker affinity for Fe³⁺ compared to deferiprone.
• However, it has enough affinity to interact with misfolded alpha-synuclein-bound iron in neurons without removing Fe³⁺ from enzymes.
• Unlike deferiprone, which forms a complex around Fe³⁺, allowing it to pass freely through membranes and be excreted in urine, ATH434 does not function this way.
• Deferiprone removes excess iron from the body (acting as a chelator).
• In contrast, ATH434 binds Fe²⁺ or Fe³⁺ without transporting it out of the cell. Instead, iron is transferred to other proteins for normal cellular functions.

2. ATH434 Converts Fe²⁺ to Fe³⁺ at a Much Slower Rate

• Pall et al. demonstrated that Fe²⁺ oxidation by ATH434 is significantly slower than with deferiprone.
• As a result:
  • More Fe²⁺ remains safely bound to ATH434 or endogenous chaperones.
  • Fewer oxygen radicals are generated.

3. ATH434 Has Direct Antioxidant Properties

• Unlike deferiprone, ATH434 possesses direct antioxidant properties.
• This may help manage oxygen radicals in diseased tissues.

I hope this was helpful. Let us know if you have any further questions.