Life Sciences & Biotechnology
Title : | Inhibition of Type II Diabetes Associated Islet Amyloid Polypeptide Aggregation by Cyclic N-substituted Oligopyrrolamide |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Molecular Biology |
Principal Investigator : | Dr. Debabrata Maity, CSIR-Indian Institute Of Chemical Technology, Hyderabad, Telangana |
Timeline Start Year : | 2023 |
Timeline End Year : | 2025 |
Contact info : | debabrataorg@gmail.com |
Details
Executive Summary : | The decline in β-cell mass and presence of Islet Amyloid Polypeptide (IAPP) amyloid plaques in islets links IAPP aggregation with Type II Diabetes (T2D) progression.1 T2D is a major concern for India as more than 77 million people (1 in 11 Indians) are suffering from diabetes, making India the most impacted after China.2 So, there is an exigency in developing anti-diabetic treatment. Modulation of IAPP aggregation can be a potential strategy to combat T2D.3 Plenty of approaches are reported but have several drawbacks.4 Macrocycles showed inhibition of amyloid formation by binding protein’s hydrophobic residues.5 But this approach is underexplored for modulating IAPP aggregation. Recently, our research showed that a macrocycle (cucurbit[7]uril, CB[7]) could inhibit IAPP aggregation (Maity et al., Chem. Eur. J., 2022, 28, e202200456).6 This is proof of the concept that the macrocyclic approach can be successful in modulating IAPP aggregation. However, the high dose (ten equivalents) requirement of CB[7] reduces its potential to be an anti-diabetic drug. In this proposed project, we will develop multi-functionalized cyclic compounds based on N-substituted oligopyrrolamide for the modulation of IAPP aggregation. It will be obtained by solid phase synthesis and followed by cyclization in solution.7 The macrocycle Backbone will consist of two tri-pyrrolamides and flexible butyl linkers. IAPP is amphipathic in nature and has three aromatic residues, F15, F23, and C-terminal Y37, two of which reside in the “hot segments”, IAPP(8–18) and IAPP(22–28), that drive peptides aggregation.8 It contains three cationic residues (K1, R11, and H18) at N-terminus, giving a net positive charge.9 The macrocycle backbone will create a hydrophobic cavity for the encapsulation of IAPP aromatic residues. N-alkylation of the pyrrole unit will incorporate functional groups like carboxylate for binding to IAPP cationic residues. Thus, the macrocycle’s binding affinity and selectivity for IAPP will be improved. A macrocycles library having symmetric and non-symmetric functionalities will be synthesized for structural activity relationship (SAR) studies. Thioflavin-T amyloid kinetic assay will be employed to find the ‘hit’ macrocycle which will inhibit IAPP aggregation at a lower dose. Data will be further confirmed by TEM imaging. Circular dichroism studies and NMR studies will elucidate the mechanism of inhibition. A theoretical calculation will be performed to find the mode and type of interactions between them. The efficiency of the best inhibitor will be studied for the protection of pancreatic β-cells (RIN) from the toxicity of IAPP aggregation with the help of a specialized group in this area (in or outside of the institute). The macrocycle inhibition efficiency will also be compared with the non-cyclic version of the compound. After the successful completion of this project, this strategy will be tested to modulate other amyloidogenic protein aggregation. |
Total Budget (INR): | 30,91,560 |
Organizations involved