Gold-containing compounds target an apicomplexan Thioredoxin reductase: Disclosing reactivity through structural and...

Area of Science:

• Parasitology
• Medicinal Chemistry
• Drug Discovery

Background:

• Cryptosporidium causes severe diarrhea, with limited treatment options, especially for vulnerable populations.
• The parasite's reliance on the thioredoxin reductase/thioredoxin (TrxR/Trx) system for redox balance presents a unique drug target.
• Current treatments like nitazoxanide show poor efficacy in key patient groups.

Purpose of the Study:

• To investigate the potential of gold-containing compounds as inhibitors of Cryptosporidium parvum TrxR (CpTrxR).
• To explore the reactivity of CpTrxR's unique redox sites with pharmacologically relevant gold chemotypes.
• To establish gold-based scaffolds as a foundation for novel anti-Cryptosporidium therapeutics.

Main Methods:

• Utilized six structurally diverse gold compounds to probe CpTrxR activity.
• Employed X-ray crystallography and mass spectrometry to elucidate inhibition mechanisms.
• Conducted functional studies to assess the impact of compound binding on parasite viability.

Main Results:

• Gold compounds demonstrated inhibition of CpTrxR by targeting distinct redox-active cysteine motifs.
• Inhibition occurred at both the conserved N-terminal and the apicomplexan-specific C-terminal sites.
• The diverse chemical properties of gold compounds enabled selective targeting of CpTrxR.

Conclusions:

• CpTrxR is a viable and parasite-selective drug target for Cryptosporidium infections.
• Gold-based compounds show significant promise as a new class of anti-Cryptosporidium therapeutics.
• This study provides a strong foundation for developing novel gold-based drugs against cryptosporidiosis.