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

• Published in: Bioorganic & medicinal chemistry Vol. 97; p. 117538
• Main Authors: Shinde, Suchita Dattatray, Behera, Santosh Kumar, Kulkarni, Neeraj, Dewangan, Bhaskar, Sahu, Bichismita
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.01.2024
• Subjects: Alzheimer Disease - drug therapy; Amyloid; Amyloid beta-Peptides - chemistry; Biochemistry & Molecular Biology; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Copper - chemistry; Copper - pharmacology; Dipeptides - pharmacology; Ferric Compounds; Humans; Ions; Life Sciences & Biomedicine; Metals; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; A beta aggregation inhibitor; Anti-oxidant; IN-SILICO; Metal chelator; Squaramides; Bifunctional backbone modified dipeptide; PROMOTES; SQUARIC ACID; ALZHEIMERS; PEPTIDE; Alzhiemer's disease (AD); Aβ aggregation inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2023.117538

Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (A beta) 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 A beta 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 A beta 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 A beta peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the A beta peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the A beta peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of A beta peptide aggregation, the selected dipeptides were found to possess antioxidant 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.