Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aß) aggregation inhibitors.

ABSTRACT

Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aß) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aß peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aß peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aß peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aß peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aß peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aß peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.