Inorganic Biochemical Aspect on Amyloid-β Peptides

Undergraduate #168
Discipline: Chemistry and Chemical Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)

Jose A. Rosales - University of Texas at El Paso
Co-Author(s): Mahesh Narayan, University of Texas at El Paso, El Paso, TX Emmanuel Gras, CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099 31077 Toulouse Cedex 4, France Christelle Hureau, CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099 31077 Toulouse Cedex 4, France

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Alzheimer’s disease (AD) is the conventional basis of dementia in the senior populace with an occurrence of 30 million individuals globally, therefore, an improvement of therapeutic remedies is required. This necessitates an interpretation of the treatment concerning the prescription selection and the biological parameters. In AD, aggregation of the amyloid-β peptide (Aβ) creates amyloid plaques that have been studied to be a principal development and a premature consequence in the pathology. Metal ions such as Cu(I/II) and Zn(II) are associated with the occurrence of Aβ aggregation. In addition, Cu due to its redox capability produces Reactive Oxygen Species (ROS) that contribute to the oxidative stress observed in AD. For this main reason, it is considered as the therapeutic target of choice. The objectives of this study are proposing, synthesizing and investigating novel drug candidates proficient at selectively targeting Cu(II)-Aβ interactions within the synaptic cleft where Zn is contained and to interrupt the Cu(II)-Aβ interactions participating in the ROS production and Aβ aggregation. A water-soluble salophen complex with D-glucose moieties was synthesized and characterized to have more rigidity and that could cross the blood brain barrier. Semi-empirical PM3/PM6 energy calculations were done on AMPAC to find the ΔGfree and ΔGbound of the ligand with Zn/Cu. From these calculations, ΔGcoord was found to determine the coordination energy available to create the Zn/Cu complex with the ligand. The energy calculations indicate that the Zn-salophen complex is more stable than the Cu-salophen complex according to their ΔGcoord values. This stipulates a conclusion that the Zn-salophen complex can be formed with minimal energy upon the ligand binding to the metal and is more selective towards Zn. Although the ΔGbound of the Cu-salophen complex offers less energy than the Zn-salophen complex upon binding, there are other factors to consider, e.g. H-bonding, electrostatics, solvation, etc.

Abstract.docx

Funder Acknowledgement(s): NSF Grant CHE 1560390 and HRD 1202008 ; Lousiana State University iREU program ; UT System LSAMP

Faculty Advisor: Dr. Christelle Hureau, christelle.hureau@lcc-toulouse.fr

Role: A water-soluble salophen complex with D-glucose moieties was synthesized and characterized to have more rigidity and that could cross the blood brain barrier. Semi-empirical PM3/PM6 energy calculations were done on AMPAC to find the ΔGfree and ΔGbound of the ligand with Zn/Cu. From these calculations, ΔGcoord was found to determine the coordination energy available to create the Zn/Cu complex with the ligand.