Inhibition of Abeta42 aggregation by helix stabilizing peptidomimetic biomaterials

University Of South Florida, Tampa FL

Investigators

Abstract

Alzheimer’s disease (AD) is the most devastating dementia of global concern. Although the mechanism of AD pathogenesis is still under debate, it is agreed that Aβ aggregation are prominent hallmarks and the major risk of AD due to their toxicity to neurons. Therefore, Aβ aggregates, particularly oligomers, are the potential targets for the intervention of AD, as targeting and removal of Aβ fibrils or plaques is expected to eliminate the neuronal toxicity of Aβ aggregates. However, eradication of total Aβ peptides by therapeutic antibodies could lead to severe side effects, whereas anti-Aβ aggregation by β-sheet mimetics could only prevent or delay the process of aggregation process and could not disrupt the formed/existing Aβ aggregation. Therefore, development of more effective molecular probes that not only prevent but also disrupt Aβ fibril formation is still in an urgent need. In contrast to β-sheet mimetics to block Aβ fibrillar growth, recently we designed a class of peptide hybrid biomaterials that can specifically interact and stabilize Aβ helical conformation, thereby shifting the equilibrium of Aβ aggregation into off-pathway monomeric structure, leading to both prevention and disruption of Aβ aggregation. The lead compound could completely restore cell viability and boost the levels of neuronal PSD-95 and synaptophysin reduced by Aβ42 in primary neurons, and vastly prevent memory impairment in 5xFAD AD transgenic mice. Moreover, the lead compound could significantly mitigate mitochondrial and cell stress, and remarkably alleviate the systemic inflammation induced by amyloid pathology in the mice. As such, our long- term goal is to develop novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, the first step to achieve the long-term goal, is to advance our preliminary work by rationally designing structurally related analogues of the current lead, so as to identify and develop more potent and effective peptidomimetics that can prevent and disrupt Aβ aggregation both in vitro and in vivo by helical Aβ42 binding and stabilization. We will first design helical peptidic foldamer bearing diverse functional groups and closely mimic the binding pattern of our lead compound. Then we will use our established in vitro assays such as 2D-NMR, EMS-IMS, CD, TEM, and other kinetic binding assays to identify and optimize our designed compounds that target and inhibit the aggregation of Aβ peptides. The compounds with activity equivalent or better than the lead compound will be used to study their ability to inhibit Aβ pathology both in vitro and in vivo. The proposed study is significant because there is no effective strategy for AD diagnosis and prevention. Our research will provide molecules with novel mechanism to unravel AD pathogenies and to develop potential molecular probes and therapeutic agents for cure of AD. The proposed research is innovative because we not only provide a new strategy for the development of novel class of peptidomimetics that prevent and disrupt Aβ aggregation, in addition, this approach of rational design for the recognition of Aβ surface can be easily extended to identify new materials targeting other amyloid diseases such as Huntington’s disease and diabetes diseases.