Computationally Designed Molecules Modulate ALS-Related Amyloidogenic TDP-43_307-319 Aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Computational Chemistry

Background:

• Abnormal aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a hallmark of neurodegenerative diseases such as ALS.
• The C-terminal peptide TDP-43_307-319 forms toxic hexameric cylindrin structures and amyloid fibrils.
• Targeting these toxic aggregates is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To identify and design novel TDP-43 inhibitors using the joint pharmacophore space (JPS) model.
• To evaluate the efficacy of JPS-designed molecules in preventing and dissociating TDP-43_307-319 oligomers.
• To elucidate the atomistic mechanisms of inhibition and dissociation.

Main Methods:

• Joint pharmacophore space (JPS) modeling for molecule design.
• Experimental assays: ion mobility mass spectrometry, thioflavin T fluorescence, circular dichroism, atomic force microscopy.
• Computational methods: molecular dynamics simulations.

Main Results:

• Five JPS-designed molecules successfully inhibited TDP-43_307-319 amyloid fibril formation.
• [AC0101] demonstrated superior efficacy in preventing and dissociating higher-order TDP-43 oligomers.
• Molecular dynamics revealed [AC0101]'s flexibility and hydrogen bonding potential, facilitating insertion into and disruption of the hexameric structure.

Conclusions:

• JPS-designed molecules are effective inhibitors of TDP-43_307-319 aggregation.
• [AC0101] shows significant potential as a therapeutic lead for TDP-43-related neurodegenerative diseases.
• The study proposes atomistic mechanisms for how these molecules disrupt toxic TDP-43 oligomers.