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TS4NC: Therapeutic S4N Chelation targeting Alzheimer's Disease.

Periodic Reporting for period 1 - TS4NC (TS4NC: Therapeutic S4N Chelation targeting Alzheimer's Disease.)

Période du rapport: 2021-03-01 au 2023-02-28

Despite enormous research efforts across academia and pharmaceutical industry, all clinical trials over the last decade have failed in finding a treatment for Alzheimer’s Disease (AD) which remains one of the greatest challenges in drug discovery. This neurodegenerative, progressive and irreversible brain disorder is slowly destroying the memory, cognition and ability to perform the simplest daily activities of millions of people around the world, and this number is estimated to increase to 152 million by 2050. It is suggested that healthy lifestyle with a balanced diet and both physical and mental exercise may reduce our risk of developing the condition. But the question remains, why drug development keeps failing? We believe part of the problem is that researchers focus mainly on Amyloid Cascade Hypothesis of AD, without deeper consideration of Metal Ion and Oxidative Stress Hypotheses. Herein, the TS4NC project tackled all three of them together by addressing the high level of oxidative stress produced by nonregulated redox active metal ions such as copper linked to different forms/aggregates of amyloid-β (Aβ) peptides responsible for amyloid plaque formation. This synergistic and novel strategy allowed us to conduct a comprehensive study of short peptides and shed light into discovery of the base sequence for potential drug candidate that may be involved in the redistribution and the restoration of brain biometal homeostasis.
The TS4NC project started with selecting short peptides containing three amino acids with at least one histidine within the sequence. Histidine is responsible for copper binding and its position in peptide is important because it modulates affinity of this binding. The aim of this study was to arrest oxidative stress by dissociating of copper from amyloid-βeta (Aβ) peptides performed by short peptide and deliver copper back to the cells (redistribution). Dissociation of copper from Aβ will stop oxidative stress caused by reactive oxygen species production due to copper redox cycle. At first peptide with histidine in third position (FRH) was tested but due to very high copper affinity, but it was impossible to after getting copper from Aβ to deliver it to other copper carriers, means it was too high for planned redistribution of copper. Thus, peptides with histidine at second positions (DHK, MHK and WHK) were included in this study as well, due to relatively high copper binding constant and potential ability to put copper back into its physiological cycle. Various assays have been performed to achieve objectives of this project, such as measurements using UV-Vis, Fluorescence and EPR spectroscopy and numerous cell toxicity study. Based on the overall results, DHK was selected as a final promising candidate due to its favourable copper binding leading to effective therapeutic chelation and copper redistribution, as well as oxidative protective profiles, resulting in copper homeostasis restoration.
The TS4NC project showed that conventional focus on the amyloid cascade hypothesis alone in Alzheimer’s Disease drug discovery research was too simplistic, and most methods, such as using antibodies to target amyloid aggregates or enzyme inhibitors aiming to modify the amyloid precursor protein (APP) processing did not improve cognitive function in clinical trials. Therefore, it is necessary to expand the panel of drug targets. Here, an alternative strategy is considered, focusing on the integration of metal ion hypothesis and oxidative stress hypothesis, given the connection between AD and redox metal dyshomeostasis. However, the drug candidate should not only act as a traditional metal chelator by simply eliminating metals from the organism, on the contrary, it performs as Metal–Protein Attenuating Compounds (MPACs) by redistributing and assisting in the restoration of brain biometal homeostasis. During this project, we were able to study such molecules and select one that we believe could serve as a basis for a promising drug candidate, not least due to the sequestration of Cu ions from their Aβ complexes and the arrest of their redox cycles, thus reducing oxidative stress in the neuronal cells, but also provides anti-inflammatory effects, delivers overall neuroprotection and put Cu back into normal physiological circulation. This synergistic project aimed to address a significant public health issue, Alzheimer’s Disease, and as such is of great interest to both public and private sectors. The results gathered from this study still require further investigation, but for now being able to select a promising tripeptide for further study is a positive outcome.
Schematic representation of the TS4NC project.