Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity

Abstract

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer's disease (AD) and Type-2 diabetes Mellitus (T2DM). Aggregation of specific peptides, like Aβ42 in AD and hIAPP in T2DM, causes cellular dysfunction resulting in the respective pathology. While these amyloidogenic proteins lack sequence homology, they all contain aromatic amino acids in their hydrophobic core that play a major role in their selfassembly. Targeting these aromatic residues by small molecules may be an attractive approach for inhibiting amyloid aggregation. Here, various biochemical and biophysical techniques revealed that a panel of tryptophan-galactosylamine conjugates significantly inhibit fibril formation of Aβ42 and hIAPP, and disassemble their pre-formed fibrils in a dosedependent manner. They are also not toxic to mammalian cells and can reduce the cytotoxicity induced by Aβ42 and hIAPP aggregates. These tryptophan-galactosylamine conjugates can therefore serve as a scaffold for the development of therapeutics towards AD and T2DM.

Probing TDP-43 condensation using an in silico designed aptamer

“…Interestingly, only 6% of the aggregates detected using Apt-1 were ThT-active, also at later time points, demonstrating the aptamer's ability to identify less mature oligomers that may be important in the disease pathology of TDP-43 and overcoming the limitations of current methods, such as the identification of oligomers of different size and structure. Other most commonly used approaches for the imaging and morphology studies of protein aggregates are transmission electron microscopy (TEM) 50 and atomic force microscopy (AFM) 51 . Both techniques provide qualitative and quantitative information at the nanometer level, but the former is limited in resolution and the latter requires long and complex sample preparation.…”

An explicitly designed paratope of amyloid-β prevents neuronal apoptosis in vitro and hippocampal damage in rat brain

“…3c), indicating the amyloid signature, as previously reported. 36 With the assistance of SP1, the density of Ab 42 brils was reduced in a dose-dependent manner. Also, untreated Ab 42 aggregates exhibited green-gold birefringence upon staining with Congo red (Fig.…”

Inhibition of tau amyloid formation and disruption of its preformed fibrils by Naphthoquinone–Dopamine hybrid

“…The kinetics of PHF6 (Ac-VQIVYK-NH 2 ) aggregation upon incubation with or without various concentrations of the inhibitors, NQ, DA, or NQDA (PHF6: inhibitor = 5 : 1, 1 : 1, and 1 : 5) was monitored by thioflavin S (ThS) fluorescence assay. Prior to the assay, PHF6 was monomerized by treating it with HFIP, a commonly used method to monomerize amyloidogenic proteins including Aβ 42 in AD and amylin polypeptide associated with diabetes type 2 [39,40]. The nature of the PHF6 monomers was verified immediately thereafter (at time zero) by CD (see below).…”