Conformational-specific self-assembled peptides as dual-mode, multi-target inhibitors and detectors for different amyloid proteins

Prevention and detection of misfolded amyloid proteins and their beta-structure-rich aggregates are the two promising but different (pre)clinical strategies to treat and diagnose neurodegenerative diseases including Alzheimer's diseases (AD) and type II diabetes (T2D). Conventional strategies prevent the design of new pharmaceutical molecules with both amyloid inhibition and detection functions. Here, we propose a like-interacts-like design principle to de novo design a series of new self-assembling peptides (SAPs), enabling them to specifically and strongly interact with conformationally similar beta-sheet motifs of A beta (association with AD) and hIAPP (association with T2D). Collective in vitro experimental data from thioflavin (ThT), atomic force microscopy (AFM), circular dichroism (CD), and cell assay demonstrate that SAPs possess two integrated functions of (i) amyloid inhibition for preventing both A beta and hIAPP aggregation by 34-61% and reducing their induced cytotoxicity by 7.6-35.4% and (ii) amyloid sensing for early detection of toxic A beta and hIAPP aggregates using in-house SAP-based paper sensors and SPR sensors. The presence of both amyloid inhibition and detection in SAPs stems from strong molecular interactions between amyloid aggregates and SAPs, thus providing a new multi-target model for expanding the new therapeutic potentials of SAPs and other designs with built-in amyloid inhibition and detection functions.

Automated summary

Prevention and detection of misfolded amyloid proteins and their beta-structure-rich aggregates are promising strategies for treating and diagnosing neurodegenerative diseases. The author proposes a design principle that allows new self-assembling peptides (SAPs) to interact with similar beta-sheet motifs of A beta and hIAPP, leading to both amyloid inhibition and detection functions. Experimental data show that SAPs effectively inhibit the aggregation of A beta and hIAPP and can detect toxic amyloid aggregates.