Metal-Mediated Nanobody Assemblies as Potent Alleviator of Human Islet Amyloid Polypeptide Aggregation
发布时间：2023-07-20
点击次数：
- 发表刊物：
- Materials Chemistry Frontiers
- 期号：
- 10
- ISSN号：
- 2052-1537
- DOI码：
- 10.1039/D2QM01372J
- 发表时间：
- 2023-03-02
- 影响因子：
- 8.683
- 摘要：
- he 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.
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