Clusterin is a heterodimeric glycoprotein (α- and β-chain), which has been described as an extracellular molecular chaperone. In humans, clusterin is an amyloid-associated protein, co-localizing with fibrillar deposits in several amyloidoses, including Alzheimer's disease. To clarify its potential implication in amyloid formation, we located aggregation-prone regions within the sequence of clusterin α-chain, via computational methods. We had peptide-analogues, which correspond to each of these regions, chemically synthesized and experimentally demonstrated that all of them can form amyloid-like fibrils. We also provide evidence that the same peptide-analogues can inhibit amyloid-β fibril formation, potentially making them appropriate drug candidates for Alzheimer's disease. At the same time, our findings hint that the respective aggregation-prone clusterin regions may be implicated in the molecular mechanism in which clusterin inhibits amyloid formation. Furthermore, we suggest that molecular chaperones with amyloidogenic properties might have a role in the regulation of amyloid formation, essentially acting as functional amyloids.

Type I fimbriae are the main adhesive organelles of uropathogenic Escherichia coli (UPEC), consisting of four different subunits. Their component with the most important role in establishing bacterial infections is the FimH adhesin located at the fimbrial tip. This two-domain protein mediates adhesion to host epithelial cells through interaction with terminal mannoses on epithelial glycoproteins. Here, we propose that the amyloidogenic potential of FimH can be exploited for the development of therapeutic agents against Urinary Tract Infections (UTIs). Aggregation-prone regions (APRs) were identified via computational methods, and peptide-analogues corresponding to FimH lectin domain APRs were chemically synthesized and studied with the aid of both biophysical experimental techniques and molecular dynamic simulations. Our findings indicate that these peptide-analogues offer a promising set of antimicrobial candidate molecules since they can either interfere with the folding process of FimH or compete for the mannose-binding pocket.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid-β (Aβ) peptides. The oligomeric form of Aβ is acknowledged as the most neurotoxic, propelling the pathological progression of AD. Interestingly, besides Aβ, other proteins are co-localized within amyloid plaques. Peptide analogs corresponding to the “aggregation-prone” regions (APRs) of these proteins could exhibit high-affinity binding to Aβ and significant inhibitory potential against the Aβ oligomerization process. The peptide analogs of co-localized protease, Cathepsin B, may act as such potent inhibitors. In silico studies on the complexes of the oligomeric state of Aβ and Cathepsin B peptide analogs were performed utilizing molecular docking and molecular dynamics simulations, revealing that these analogs disrupt the β-sheet-rich core of Aβ oligomers, a critical structural feature of their stability. Of the four peptide analogs evaluated, two demonstrated considerable potential by effectively destabilizing oligomers while maintaining low self-aggregation propensity, i.e., a crucial consideration for therapeutic safety. These findings point out the potential of APR-derived peptide analogs from co-localized proteins as innovative agents against AD, paving the way for further exploration in peptide-based therapeutic development.