Huy, P. D. Q. | Search bioRxiv

bioRxiv2025

A potential anti-amyloidogenic therapy for type 2 diabetes based on the QBP1 peptide

The self-assembly and aggregation of human islet amyloid polypeptide (hIAPP, or amylin) into {beta}-sheet-rich structures, such as oligomers and fibrils, are implicated in pancreatic {beta}-cell dysfunction and failure, contributing to the pathogenesis of Type 2 Diabetes (T2D). Consequently, extensive research has focused on identifying inhibitors, particularly short peptides, capable of targeting hIAPP and disrupting its amyloidogenic process, offering potential therapeutic strategies to prevent or slow T2D progression. In this study, we demonstrate the effectiveness of the anti-amyloidogenic peptide QBP1 in blocking the critical conformational transition to {beta}-structure experienced by the hIAPP monomer, thereby in preventing amyloidogenesis and in reducing the cytotoxicity associated with its amyloid forms. First, we evaluated the anti-amyloidogenic effects of QBP1 through an in vitro aggregation methods, including a Thioflavin-T binding assay, dot blotting using the oligomer-specific A11 and fibril-specific OC antibodies, and negative staining electron microscopy. To assess its cytoprotective potential of QBP1 on hIAPP-induced toxicity, we examined its effects when fused to a protein transduction domain (penetratin) in INS-1E pancreatic {beta}-cells, using viability assays and transcriptome analysis. Our results demonstrate that QBP1 effectively halts the formation of early toxic hIAPP intermediates, preventing amyloid progression and preserving {beta}-cell viability and function. Additionally, molecular dynamics simulations revealed that QBP1 stabilizes amylin through strong van der Waals interactions and {pi}-H bonds at hydrophobic and aromatic residues (i.e., W, F), forming a stable binding network that prevents aggregation. Binding free energy analysis confirmed its high affinity, driven by favourable non-polar solvation energy and optimized structural complementarity. Collectively, these findings position QBP1 as a promising therapeutic candidate for preventing islet amyloid formation and mitigating {beta}-cell dysfunction in T2D. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/652241v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1e7ed7borg.highwire.dtl.DTLVardef@1985667org.highwire.dtl.DTLVardef@509779org.highwire.dtl.DTLVardef@108a3c4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2020

A computational model to unravel the function of amyloid-β peptide in contact with a phospholipid membrane

The normal synapse activity involves the release of copper and other divalent cations in the synaptic region. These ions have a strong impact on the membrane properties, especially when the membrane has charged groups, like it is the case of synapse. In this work we use an atomistic computational model of dimyristoyl-phosphatidylcholine (DMPC) membrane bilayer. We perturb this model with a simple model of divalent cation (Mg2+), and with a single amyloid-{beta} (A{beta}) peptide of 42 residues, both with and without a single Cu2+ ion bound to the N-terminus. In agreement with experimental results reported in the literature, the model confirms that divalent cations locally destabilize the DMPC membrane bilayer, and, for the first time, that the monomeric form of A{beta} helps in avoiding the interactions between divalent cations and DMPC, preventing significant effects on the DMPC bilayer properties. These results are discussed in the frame of a protective role of diluted A{beta} peptide floating in the synaptic region. Author summaryWe modelled the behavior of a Mg2+ divalent cation, with the size of Zn2+ and Cu2+, in contact with a phosphatidyl lipid bilayer. We also modelled the monomeric amyloid-{beta} peptide 1-42, both free and Cu-loaded, the latter mimicking the final step of the binding between the peptide and the divalent cation. On the basis of the simulation results, we propose that the peptide hinders the strong interactions between the divalent cation and the membrane.

biophysics↗