Chemical Chaperones Modulate the Formation of Metabolite Assemblies

Area of Science:

• Biochemistry
• Metabolic Disorders
• Drug Discovery

Background:

• Metabolite-induced amyloid-like structures are implicated in inborn errors of metabolism (IEMs).
• The molecular mechanisms of metabolite assembly and therapeutic interventions remain largely unknown.
• Protein and peptide amyloid formation can be inhibited by chemical chaperones.

Purpose of the Study:

• To investigate the inhibitory effects of osmolytes and chemical chaperones on metabolite assemblies.
• To explore the therapeutic potential of chemical chaperones for IEMs.
• To elucidate the mechanisms underlying chaperone-mediated inhibition of metabolite self-assembly.

Main Methods:

• Combined in vivo, in vitro, and in silico approaches.
• Biophysical techniques (e.g., spectroscopy, microscopy) to study metabolite self-assembly.
• Whole-atom molecular dynamics simulations to analyze molecular interactions.

Main Results:

• Chemical chaperones inhibited metabolite amyloid-induced toxicity and reduced cellular amyloid load in yeast models.
• Direct inhibition of adenine self-assembly and altered fibril morphology were observed.
• Dimethyl sulfoxide derivatives showed efficacy in inhibiting metabolite self-assembly.
• Molecular dynamics simulations revealed the role of hydrogen bonds in osmolyte inhibition.

Conclusions:

• Chemical chaperones exhibit a dual mode of action against metabolite assemblies, suggesting therapeutic potential for IEMs.
• These findings support the rational design of novel therapeutic molecules targeting metabolite self-assembly.
• The study extends the known functional repertoire of chemical chaperones to metabolite-derived amyloids.