Rational Design of a Cu Chelator That Mitigates Cu‐Induced ROS Production by Amyloid Beta. (30th December 2021)

• Record Type: Journal Article
• Authors: Mitra, Suchitra; Talukdar, Kallol; Prasad, Pallavi; Misra, Sandeep K.; Khan, Shabana; Sharp, Joshua S.; Jurss, Jonah W.; Chakraborty, Saumen
• Is Part Of: Chembiochem. Volume 23:Number 4(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-30
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202100485
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Alzheimer's disease severely perturbs transition metal homeostasis in the brain leading to the accumulation of excess metals in extracellular and intraneuronal locations. The amyloid beta protein binds these transition metals, ultimately causing severe oxidative stress in the brain. Metal chelation therapy is an approach to sequester metals from amyloid beta and relieve the oxidative stress. Here we have designed a mixed N/O donor Cu chelator inspired by the proposed ligand set of Cu in amyloid beta. We demonstrate that the chelator effectively removes Cu from amyloid beta and suppresses reactive oxygen species (ROS) production by redox silencing and radical scavenging both in vitro and in cellulo . The impact of ROS on the extent of oxidation of the different aggregated forms of the peptide is studied by mass spectrometry, which, along with other ROS assays, shows that the oligomers are pro‐oxidants in nature. The aliphatic Leu34, which was previously unobserved, has been identified as a new oxidation site. Abstract : A rationally designed mixed Cu chelator mitigates Cu−Aβ induced reactive oxygen species formation by redox silencing and radical scavenging. The presence of oxidized amino acids in Aβ correlates to their role in the entatic state.