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Synthesis and Evaluation of Arylamides with Hydrophobic Side Chains for Insulin Aggregation Inhibition
Author(s) -
Gangarde Yogesh M.,
Das Anirban,
Ajit Jainu,
Saraogi Ishu
Publication year - 2021
Publication title -
chempluschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.801
H-Index - 61
ISSN - 2192-6506
DOI - 10.1002/cplu.202100036
Subject(s) - chemistry , small molecule , fibril , insulin , thioflavin , side chain , biophysics , peptide , protein aggregation , hydrophobic effect , ic50 , molecule , nucleation , combinatorial chemistry , biochemistry , in vitro , biology , organic chemistry , polymer , medicine , disease , alzheimer's disease , pathology , endocrinology
Insulin, a peptide hormone, forms fibrils under aberrant physiological conditions leading to a reduction in its biological activity. To ameliorate insulin aggregation, we have synthesized a small library of oligopyridylamide foldamers decorated with different combination of hydrophobic side chains. Screening of these compounds for insulin aggregation inhibition using a Thioflavin‐T assay resulted in the identification of a few hit molecules. The best hit molecule, BPAD2 inhibited insulin aggregation with an IC 50 value of 0.9 μM. Mechanistic analyses suggested that BPAD2 inhibited secondary nucleation and elongation processes during aggregation. The hit molecules worked in a mechanistically distinct manner, thereby underlining the importance of structure‐activity relationship studies in obtaining a molecular understanding of protein aggregation.