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论文类型：文章

发表刊物：Materials Chemistry Frontiers

收录刊物：SCI

卷号：7

期号：10

页面范围：2068-2077

ISSN号：2052-1537

DOI码：10.1039/D2QM01372J

发表时间：2023-03-02

影响因子：8.683

摘要：The misfolding and aggregation of peptides and proteins into β-sheet-enriched amyloid fibrils has been implicated in many human diseases. Inhibition of protein aggregation by engineered nanobodies has shown great promise in the treatment of amyloid-associated diseases. Taking type 2 diabetes associated human islet amyloid polypeptide (IAPP) aggregation as a model system, we generated a nanobody inhibitor by grafting the IAPP peptide fragment into the complementary determining region of a parent nanobody to inhibit IAPP aggregation through homotypic interactions. In addition, we developed a facile fabrication strategy to amplify the inhibitory effects of the designed nanobody inhibitor on IAPP aggregation. By coordinating a metal cation Zn2+ with a histidine-tag-fused nanobody inhibitor M1, the achieved nanobody assemblies M1@Zn2+ can significantly enhance the binding affinity between IAPP and M1 through the multivalent effects. At low substoichiometric concentrations (20 : 1 IAPP : nanobody molar ratio), M1@Zn2+ are capable of efficiently inhibiting IAPP aggregation, alleviating IAPP-induced cytotoxicity and downregulating ROS generation. This strategy represents an innovative attempt to design high-efficiency amyloid antibody inhibitors with enhanced therapeutic effects for the treatment of amyloid diseases.