Kalita Sourav, Kalita Sujan, Paul Ashim, Shah Manisha, Kumar Sachin, Mandal Bhubaneswar
Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India
Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati Assam-781039 India.
RSC Chem Biol. 2021 Jan 15;2(1):266-273. doi: 10.1039/d0cb00178c. eCollection 2021 Feb 1.
Amylin or hIAPP, together with insulin, plays a significant role in glucose metabolism. However, it undergoes β-sheet rich amyloid formation associated with pancreatic β-cell dysfunction leading to type-2 diabetes (T2D). Recent studies suggest that restricting β-sheet formation in it may halt amyloid formation, which may limit the risk for the disease. Several peptide-based inhibitors have been reported to prevent aggregation. However, most of them have limitations, including low binding efficiency, active only at higher doses, poor solubility, and proteolytic degradation. Insertion of non-coded amino acids renders proteolytically stable peptides. We incorporated a structurally rigid β-amino acid, Anthranilic acid (Ant), at different sites within the central hydrophobic region of hIAPP and developed two singly mutated hIAPP peptidomimetics. These peptidomimetics inhibited the amyloid formation of hIAPP substantially even at low concentration, as evident from ThT, CD, FT-IR, TEM, and Congo red staining birefringence results. These peptidomimetics also disrupted the preformed aggregates formed by hIAPP into non-toxic species. These β-amino acid-based peptidomimetics can be an attractive scaffold for therapeutic design towards T2D or other protein misfolding diseases.
胰淀素或人胰岛淀粉样多肽（hIAPP）与胰岛素一起在葡萄糖代谢中发挥重要作用。然而，它会形成富含β-折叠的淀粉样蛋白，与胰腺β细胞功能障碍相关，导致2型糖尿病（T2D）。最近的研究表明，限制其β-折叠的形成可能会阻止淀粉样蛋白的形成，这可能会降低患病风险。据报道，几种基于肽的抑制剂可防止聚集。然而，它们中的大多数都有局限性，包括结合效率低、仅在高剂量时才有活性、溶解度差以及蛋白水解降解。插入非编码氨基酸可使肽具有蛋白水解稳定性。我们在hIAPP的中央疏水区域的不同位点掺入了一种结构刚性的β-氨基酸，邻氨基苯甲酸（Ant），并开发了两种单突变的hIAPP拟肽。从硫代黄素T（ThT）、圆二色性（CD）、傅里叶变换红外光谱（FT-IR）、透射电子显微镜（TEM）和刚果红染色双折射结果可以明显看出，这些拟肽即使在低浓度下也能显著抑制hIAPP的淀粉样蛋白形成。这些拟肽还能将hIAPP形成的预先存在的聚集体破坏成无毒物种。这些基于β-氨基酸的拟肽可能是用于治疗T2D或其他蛋白质错误折叠疾病的有吸引力的支架。
