Peptidomimetic-Based Vesicles Inhibit Amyloid-β Fibrillation and Attenuate Cytotoxicity

Abstract

An interruption in Aβ homeostasis leads to the deposit of neurotoxic amyloid plaques and is associated with Alzheimer's disease. A supramolecular strategy based on the assembly of peptidomimetic agents into functional vesicles has been conceived for the simultaneous inhibition of Aβ 42 fibrillation and expedited clearance of Aβ 42 aggregates. Tris-pyrrolamide peptidomimetic, ADH-353, contains one hydrophobic N-butyl and two hydrophilic N-propylamine side chains and readily forms vesicles under physiological conditions. These vesicles completely rescue both mouse neuroblastoma N2a and human neuroblastoma SH-SY5Y cells from the cytotoxicity that follows from Aβ 42 misfolding likely in mitochondria. Biophysical studies, including confocal imaging, demonstrate the biocompatibility and selectivity of the approach toward this aberrant protein assembly in cellular milieu.

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease

“…To investigate further the selective binding of LS-4 and Pre-LS-4 to the various Aβ species, these compounds were used in ex vivo fluorescence imaging studies. The brain sections of 7-month old 5xFAD transgenic mice, which rapidly develop severe amyloid pathology, were stained with LS-4 and then sequentially stained with either Congo Red (a well-known fluorescent dye) or immunostained with the HJ3.4 antibody, which can bind to a wide range of Aβ species, or with an Aβ oligomer-specific monoclonal antibody (OMAB), which specifically binds to Aβ oligomers. ,,, A strong fluorescence signal was detected upon staining of the 5xFAD mouse brain sections with LS-4 (Figure , left panels), with an excellent colocalization with the immunofluorescence of OMAB (Pearson’s correlation coefficient of 0.89). For the brain sections immunostained with HJ3.4, the colocalization of the LS-4 signal was also high (Pearson’s correlation coefficient 0.78), since the HJ3.4 antibody can bind to a wide range of Aβ species.…”

Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

“…Recently, peptidomimetic-based amphiphilic compounds were shown to inhibit Aβ fibrillation process and attenuate Aβ cytotoxicity in both neuroblastoma N2a and human neuroblastoma SH-SY5Y cells. 22 Moreover, our group also successfully developed an amphiphilic small molecule, LS-4, that can serve as a therapeutic and imaging agent for Aβ oligomers in AD. 23 LS-4 was synthesized by attaching a hydrophilic azamacrocycle, 2,4-dimethyl-1,4,7-triazacyclononane (Me2HTACN), to a hydrophobic distyryl stilbene derivative.…”

Combating amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

“…Natural peptide-based amyloid inhibitors offer numerous advantages over small molecule inhibitors [18][19][20][21] owing to their biological origin, biocompatibility, target-specific binding, sequence variability and ease of synthesis. [22][23][24][25][26][27][28][29] Short peptides with 16 KLVFF 20 derived from Ab42 have been shown to inhibit Ab aggregation. [30][31][32][33] The propensity of natural peptides for proteolytic cleavage and self-aggregation has led to the development of peptidomimetics-based inhibitors such as peptoids and cyclic peptides.…”