Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties

Abstract

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo.

Exploring Peptido‐Nanocomposites in the Context of Amyloid Diseases

“…To fullfil amyloid binding and cellular uptake, CPPs typically are designed to possess a hydrophobic N‐terminus and a hydrophilic cationic C‐terminus. PrP (prion protein)‐derived CPPs entailed an enhanced BBB‐crossing capacity, while the affinity of CPPs for prions/amyloid peptide segments prevented amyloidosis and prion formation to supress their neurotoxicity [176–178] . The CPP derived from PrP consisted of two parts: a hydrophobic signal segment (PrP residues: 1–22) and a polycationic segment rich in arginine and lysine (PrP residues: 23–28 (KKRPKP)).…”

“…PrP (prion protein)-derived CPPs entailed an enhanced BBB-crossing capacity, while the affinity of CPPs for prions/ amyloid peptide segments prevented amyloidosis and prion formation to supress their neurotoxicity. [176][177][178] The CPP derived from PrP consisted of two parts: a hydrophobic signal segment (PrP residues: 1-22) and a polycationic segment rich in arginine and lysine (PrP residues: 23-28 (KKRPKP)). The N-terminus of PrP became protonated in neutral pH to play a crucial role in protein internalization by enabling the reprocess between the cell surface and endosomal sections.…”

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

“…As both the Aβ and dynorphin peptides are known to interact with membranes [45] , [46] – Aβ is even produced by enzymatic cleavage of the AβPP (Amyloid-β precursor protein) membrane protein - it appears likely that in vivo, the two types of peptides will encounter each other and interact in membrane locations. In the amyloid field, the study of peptide-peptide cross-interactions is key [3] , [11] , [12] , [47] , [48] to characterize the physiological environment and determine which players can act as pro-amyloid or anti-amyloid agents opening new therapeutic windows in neurodegenerative disorders, such as studies on the cross-interaction between α-synuclein and endogenous peptides used as peptide-therapeutic scaffolds for Parkinson’s disease [49] .…”

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases

“…17 Later, it was revealed that replacing the original signal sequence of PrP with the signal sequence of neuronal cell adhesion molecule 1 (NCAM1) does not affect the antiprion activity. 180 In a similar study, the same CPP, named NCAM-PrP, containing the hydrophobic signal sequence fused to a polycationic hexapeptide was designed to inhibit Aβ amyloid aggregation. The interaction of Aβ with NCAM-PrP resulted in the formation of heterooligomeric complexes and an aggregation state that was different from amyloid aggregates formed by Aβ homo-oligomers.…”

“…179 Gold NPs functionalized with CPPs have also been used as delivery systems due to their unique theragnostic properties combined with their high biocompatibility and small size, which allow them to penetrate deep into tissues. 180 In this context, a transmembrane peptide-chondroitin sulfate-gold nanoparticle (Tat-CS@Au) was synthesized, and its anti-AD properties were investigated in vitro. The cellular uptake of Tat-CS@Au was confirmed using SH-SY5Y cells.…”