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Papers by Yogesh Mahadev Gangarde

Collection of Czechoslovak Chemical Communications, May 1, 2021

Insulin, a peptide hormone, forms fibrils under aberrant physiological conditions leading to a re... more 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 IC50 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.

International Journal of Biological Macromolecules, Oct 1, 2022

Molecular Pharmaceutics, Apr 29, 2020

Amyloidosis is a well-known, but poorly understood phenomenon caused by the aggregation of protei... more Amyloidosis is a well-known, but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications, and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity, and remained functionally active in regulating cell proliferation in cultured Drosophila wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.

Insulin, a peptide hormone, is susceptible to amyloid formation upon exposure to aberrant physiol... more Insulin, a peptide hormone, is susceptible to amyloid formation upon exposure to aberrant physiological conditions, resulting in a loss of its bioactivity. For mitigating insulin aggregation, we report a molecule called PADS , which completely inhibited insulin fibril formation, and preserved insulin in its soluble form. Circular Dichroism spectroscopy showed that PADS was able to maintain the native structure of insulin, thus acting as a chemical chaperone. Seeded aggregation kinetics suggest that PADS inhibited primary nucleation events during aggregation. This is consistent with molecular docking results which suggest that PADS binds strongly to native insulin monomers/dimers. Through a competitive binding experiment with 'LVEALYL' peptide, we conclude that PADS likely binds to the amyloid prone B11-B17 residues of insulin thereby preventing its aggregation. PADS was also effective in disaggregating preformed insulin fibrils to non-toxic species. PADS treated insulin was functional as indicated by its ability to phosphorylate Akt. PADS was also highly effective in preventing the aggregation of insulin biosimilars. The low cellular cytotoxicity of PADS , and amelioration of aggregation-induced toxicity by PADS treated insulin further highlights its potential as an effective chemical chaperone.

Supramolecular interactions play a fundamental role in the biochemistry of all living organisms. ... more Supramolecular interactions play a fundamental role in the biochemistry of all living organisms. In natural systems, diverse functional architectures assembled noncovalently from a handful of chemical components carry out life functions in an efficient, reversible, flexible, and adaptable manner. Chemists, equipped with a much larger library of building blocks, have tried to recreate such functional assemblies albeit with limited success so far. Nonetheless, synthetic supramolecular assemblies have played an important role in probing, informing, and manipulating biology. In this article, we discuss representative examples of supramolecular assemblies that interact with DNA, RNA, or proteins in a biologically relevant context.

ACS omega, Oct 20, 2020

Amphiphilic assemblies made from diverse synthetic building blocks are well known for their biome... more Amphiphilic assemblies made from diverse synthetic building blocks are well known for their biomedical applications. Here, we report the synthesis of gemini-type amphiphilic molecules that form stable assemblies in water. The assembly property of molecule M2 in aqueous solutions was first inferred from peak broadening observed in the proton NMR spectrum. This was supported by dynamic light scattering and transmission electron microscopy analysis. The assembly formed from M2 (M2 agg) was used to solubilize the hydrophobic drugs curcumin and doxorubicin at physiological pH. M2 agg was able to effectively solubilize curcumin as well as protect it from degradation under UV irradiation. Upon solubilization in M2 agg , curcumin showed excellent cell permeability and higher toxicity to cancer cells over normal cells, probably because of enhanced cellular uptake and increased stability. M2 agg also showed pH-dependent release of doxorubicin, resulting in controlled toxicity on cancer cell lines, making it a promising candidate for the selective delivery of drugs to cancer cells.

Collection of Czechoslovak Chemical Communications, May 1, 2021

Insulin, a peptide hormone, forms fibrils under aberrant physiological conditions leading to a re... more 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 IC50 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.

International Journal of Biological Macromolecules, Oct 1, 2022

Molecular Pharmaceutics, Apr 29, 2020

Amyloidosis is a well-known, but poorly understood phenomenon caused by the aggregation of protei... more Amyloidosis is a well-known, but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications, and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity, and remained functionally active in regulating cell proliferation in cultured Drosophila wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.

Insulin, a peptide hormone, is susceptible to amyloid formation upon exposure to aberrant physiol... more Insulin, a peptide hormone, is susceptible to amyloid formation upon exposure to aberrant physiological conditions, resulting in a loss of its bioactivity. For mitigating insulin aggregation, we report a molecule called PADS , which completely inhibited insulin fibril formation, and preserved insulin in its soluble form. Circular Dichroism spectroscopy showed that PADS was able to maintain the native structure of insulin, thus acting as a chemical chaperone. Seeded aggregation kinetics suggest that PADS inhibited primary nucleation events during aggregation. This is consistent with molecular docking results which suggest that PADS binds strongly to native insulin monomers/dimers. Through a competitive binding experiment with 'LVEALYL' peptide, we conclude that PADS likely binds to the amyloid prone B11-B17 residues of insulin thereby preventing its aggregation. PADS was also effective in disaggregating preformed insulin fibrils to non-toxic species. PADS treated insulin was functional as indicated by its ability to phosphorylate Akt. PADS was also highly effective in preventing the aggregation of insulin biosimilars. The low cellular cytotoxicity of PADS , and amelioration of aggregation-induced toxicity by PADS treated insulin further highlights its potential as an effective chemical chaperone.

Supramolecular interactions play a fundamental role in the biochemistry of all living organisms. ... more Supramolecular interactions play a fundamental role in the biochemistry of all living organisms. In natural systems, diverse functional architectures assembled noncovalently from a handful of chemical components carry out life functions in an efficient, reversible, flexible, and adaptable manner. Chemists, equipped with a much larger library of building blocks, have tried to recreate such functional assemblies albeit with limited success so far. Nonetheless, synthetic supramolecular assemblies have played an important role in probing, informing, and manipulating biology. In this article, we discuss representative examples of supramolecular assemblies that interact with DNA, RNA, or proteins in a biologically relevant context.

ACS omega, Oct 20, 2020

Amphiphilic assemblies made from diverse synthetic building blocks are well known for their biome... more Amphiphilic assemblies made from diverse synthetic building blocks are well known for their biomedical applications. Here, we report the synthesis of gemini-type amphiphilic molecules that form stable assemblies in water. The assembly property of molecule M2 in aqueous solutions was first inferred from peak broadening observed in the proton NMR spectrum. This was supported by dynamic light scattering and transmission electron microscopy analysis. The assembly formed from M2 (M2 agg) was used to solubilize the hydrophobic drugs curcumin and doxorubicin at physiological pH. M2 agg was able to effectively solubilize curcumin as well as protect it from degradation under UV irradiation. Upon solubilization in M2 agg , curcumin showed excellent cell permeability and higher toxicity to cancer cells over normal cells, probably because of enhanced cellular uptake and increased stability. M2 agg also showed pH-dependent release of doxorubicin, resulting in controlled toxicity on cancer cell lines, making it a promising candidate for the selective delivery of drugs to cancer cells.