Implications of excluded volume for chemical inhibition of protein fibrillation

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 12; p. 129704
• Main Author: Minton, Allen P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2020
• Subjects: Algorithms; Amyloid - antagonists & inhibitors; Amyloid - metabolism; couplings; Drug development; Humans; Kinetics; Macromolecular crowding; Models, Biological; prediction; Protein Aggregates - drug effects; Protein fibrillation; proteins; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; wills; Macromolecular crowding; Drug development; Protein fibrillation
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129704

Two quantitative models for the effect of high total macromolecular volume occupancy (‘macromolecular crowding’) upon the chemical inhibition of protein fibrillation are presented. The first assumes that fibrillation is reversible, and the second assumes that fibrillation is irreversible. Both models predict that small molecule inhibitors will be less effective in crowded media than in dilute media, whereas macromolecular inhibitors are likely to retain their efficiency in crowded media. It is suggested that the coupling of one or more small-molecule inhibitors to an “inert” macromolecular support will increase inhibition efficiency in crowded media. •Excluded volume can interfere with the efficacy of a small molecule inhibitor of pathogenic protein fibrillation.•The larger the inhibitor, the less interference to inhibition due to excluded volume.•The efficacy of a small inhibitor may be enhanced by coupling multiple molecules of the inhibitor to a macromolecular scaffold.