Abstract
A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.
Highlights
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease estimated to affect over 44 million people worldwide, with a devastating impact on patients, their loved ones and caregivers, as well as vast social and economic consequences (Alzheimer’s Association, 2021)
Mechanistic contributions of protein aggregation to the pathogenesis of AD are still contested, targeting protein aggregation remains a central priority in drug development; the recent approval of the amyloid-beta-lowering human monoclonal antibody Aducanumab by the United States Food and Drug Administration (FDA) represents the first drug to be approved by the FDA for the treatment of AD in 18 years
It is likely that the increased efficacy of RI-OR2-TAT as an inhibitor of Aβ42 aggregation was mediated by the arginine content of TAT, through: (a) greater capacity for hydrogen bonding imparted by the arginine residues of the TAT peptide, facilitating a higher number of electrostatic interactions between the inhibitory peptide and Aβ42; (b) increased cationic charge of the RI-OR2-TAT peptide conferred by the arginine-rich TAT component, driving further chargebased repulsion of bound Aβ42 monomers; and (c) the increased length of the inhibitory peptide likely causing greater steric and/or electrostatic interference between monomers of Aβ42, preventing their self-association
Summary
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease estimated to affect over 44 million people worldwide, with a devastating impact on patients, their loved ones and caregivers, as well as vast social and economic consequences (Alzheimer’s Association, 2021). A range of therapeutic approaches for AD-associated proteopathies are in various stages of development, including enzyme inhibitors targeting the production pathway of amyloid-beta (Kumar et al, 2018), gene silencing technologies to limit the expression of pro-aggregatory mutant tau proteins (Miller et al, 2004), kinase inhibitors aimed at preventing the pro-aggregatory hyperphosphorylation of tau, passive and active immunotherapies developed to drive protein clearance, and small molecule inhibitors of protein aggregation These strategies are comprehensively reviewed in the literature (Hardy and De Strooper, 2017; Congdon and Sigurdsson, 2018; Pedrini et al, 2019). We discuss the unique properties of arginine in modulating protein aggregation, as well as arginine-rich peptides, and peptides which have employed arginine as a key residue, in targeting the proteopathies associated with AD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
