Synergistic Inhibition of Protein Fibrillation by Proline and Sorbitol: Biophysical Investigations

Abstract

We report here interesting synergistic effects of proline and sorbitol, two well-known chemical chaperones, in the inhibition of fibrillation of two proteins, insulin and lysozyme. A combination of many biophysical techniques has been used to understand the structural morphology and modes of interaction of the chaperones with the proteins during fibrillation. Both the chaperones establish stronger polar interactions in the elongation and saturation stages of fibrillation compared to that in the native stage. However, when presented as a mixture, we also see contribution of hydrophobic interactions. Thus, a co-operative adjustment of polar and hydrophobic interactions between the chaperones and the protein surface seems to drive the synergistic effects in the fibrillation process. In insulin, this synergy is quantitatively similar in all the stages of the fibrillation process. These observations would have significant implications for understanding protein folding concepts, in general, and for designing combination therapies against protein fibrillation, in particular.

Review of the current state of protein aggregation inhibition from a materials chemistry perspective: special focus on polymeric materials

“…In another study, Choudhary et al reported the inhibition of the protein fibrillation of lysozyme and insulin by proline and sorbitol. 376 Proline contains a closed ring structure in its side chain which has a hydrophobic surface, which enables it to interact with proteins through hydrophobic interactions.…”

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

“…Sorbitol may act as a protein chaperone. Indeed, sorbitol has been recently reported to inhibit protein fibrillation and stabilize misfolded polypeptides (Choudhary, Save, Kishore, & Hosur, 2016; Roy & Bhat, 2018), Interestingly, it has been postulated that the decreased yield of properly folded PMP22 at the cell membrane may be a driver for CMT1A characteristic dysmyelination (Mittendorf et al., 2017; Schlebach et al., 2015).…”

Chain Compaction and Synergistic Destabilization of Globular Proteins by Mixture of Denaturants

“…This needs further detailed residue‐level analysis. Generally, the synergistic effect of mixture of osmolytes enhances the solubility of proteins and inhibits protein fibril formation as well …”

“…Generally, the synergistic effect of mixture of osmolytes enhances the solubility of proteins [13] and inhibits protein fibril formation as well. [14] Similarly, the extent of destabilization attained by the proteins against Gdm-induced denaturation (ΔΔG unf ), in the presence of varying concentrations of Arg, was also calculated. ΔΔG unf = (ΔG unf in the presence of Arg -ΔG unf in the absence of Arg).…”