Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

Abstract

Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors. Herein, we provide a perspective of this therapeutic route with emphasis on small molecules and peptide-based drugs in two diverse diseases, PD and SCD, aiming at establishing links among proposed aggregation inhibitors. The small and large length-scale regimes of the hydrophobic effect are discussed in light of the importance of hydrophobic interactions in proteinopathies. Some simulation results are reported on model peptides, illustrating the impact of hydrophobic and hydrophilic groups in water's hydrogen-bond network with an impact on drug binding. The seeming importance of aromatic rings and hydroxyl groups in protein-aggregation-inhibitor-drugs is emphasized along with the challenges associated with some inhibitors, limiting their development into effective therapeutic options, and questioning the potential of this therapeutic route.

Cyclic Peptides as Aggregation Inhibitors for Sickle Cell Disease

“…Thus, seven CPs were designed based on the replacement of two alternating Val residues by Glu, Phe, Asp, and/or Lys. The choice of Phe was related with the presence of Phe85 in the pocket, thus, potentially allowing establishing -stacking interactions, and the fact that several drugs found to inhibit protein aggregation, including HbS 33,36 , have aromatic rings. Glu and Asp were chosen under the premise that these amino acids could hinder aggregation by destabilizing protein-protein salt bridges next to the pocket, whereas Lys was chosen because it can form a salt bridge with Asp73 in the pocket (see Fig.…”

“…https://doi.org/10.26434/chemrxiv-2023-qrzl0 ORCID: https://orcid.org/0000-0003-1704-2242 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0 Over the years, several potential therapeutic strategies have been explored 10,11,31,33,34 , namely, (i) the decrease of the intra-cellular HbS concentration, (ii) the decrease of the concentration of the allosteric effector, 2,3-diphosphoglycerate, increasing the solubility of HbS and destabilizing the fibers, (iii) the shift of the allosteric equilibrium toward the R-state, and (iv) the impediment of key protein-protein contacts in the fibers. Recently, a high-throughput assay encompassing 12,657 compounds of the Scripps ReFRAME drug repurposing library, was reported 35 .…”

“…Metaferia et al 35 found 106 compounds with antisickling activity, acting through some (unknown) of the abovementioned MOA. These small molecules, and other potential drugs with aggregation inhibitory properties have been recently reviewed in connection with aggregation inhibitors for neurodegenerative diseases 33 .…”

“…The antisickling activity of amino acids and linear peptides were also long assessed 33,[36][37][38][39] . An important conclusion from these studies was that peptides with multi-aromatic residues have a higher https://doi.org/10.26434/chemrxiv-2023-qrzl0 ORCID: https://orcid.org/0000-0003-1704-2242 Content not peer-reviewed by ChemRxiv.…”

The impact of diabetes in cognitive impairment: A review of current evidence and prospects for future investigations

“…AGEs, formed through non-enzymatic glycation of proteins or lipids exposed to aldose sugars, elevated oxidative stress and inflammation. [51,52] This leads to increased amyloid beta-42 (Aβ 42) production. Microglial clearance of Aβ 42, hindered in diabetes, results in greater Aβ accumulation and inflammation.…”