Department of Chemistry, New York University, New York, NY 10003, USA.
Present Address: Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, 500007, India.
Chemistry. 2022 Jul 6;28(38):e202200456. doi: 10.1002/chem.202200456. Epub 2022 May 31.
Two "hot segments" within an islet amyloid polypeptide are responsible for its self-assembly, which in turn is linked to the decline of β-cells in type 2 diabetes (T2D). A readily available water-soluble, macrocyclic host, cucurbit[7]uril (CB[7]), effectively inhibits islet amyloid polypeptide (IAPP) aggregation through ion-dipole and hydrophobic interactions with different residues of the monomeric peptide in its random-coil conformation. A HSQC NMR study shows that CB[7] likely modulates IAPP self-assembly by interacting with and masking major residues present in the "hot segments" at the N terminus. CB[7] also prevents the formation of toxic oligomers and inhibits seed-catalyzed fibril proliferation. Importantly, CB[7] recovers rat insulinoma cells (RIN-m) from IAPP-assembly associated cytotoxicity.
两个胰岛淀粉样多肽的“热点片段”负责其自组装，而自组装又与 2 型糖尿病 (T2D) 中β细胞的衰退有关。一种易于获得的水溶性大环主体葫芦脲[7]（CB[7]）通过与单体肽在其无规卷曲构象中的不同残基的离子偶极和疏水相互作用，有效地抑制胰岛淀粉样多肽（IAPP）聚集。HSQC NMR 研究表明，CB[7]可能通过与 N 端“热点片段”中存在的主要残基相互作用并掩盖这些残基来调节 IAPP 自组装。CB[7]还可以防止形成毒性寡聚物并抑制种子催化的纤维增殖。重要的是，CB[7]可使大鼠胰岛细胞瘤 (RIN-m) 细胞从与 IAPP 组装相关的细胞毒性中恢复。
