Issue 10, 2023

Metal-mediated nanobody assemblies as potent alleviators of human islet amyloid polypeptide aggregation

Abstract

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.

Graphical abstract: Metal-mediated nanobody assemblies as potent alleviators of human islet amyloid polypeptide aggregation

Supplementary files

Article information

Article type
Research Article
Submitted
30 Dec 2022
Accepted
01 Mar 2023
First published
02 Mar 2023

Mater. Chem. Front., 2023,7, 2068-2077

Metal-mediated nanobody assemblies as potent alleviators of human islet amyloid polypeptide aggregation

L. Zhao, L. Luo and F. Meng, Mater. Chem. Front., 2023, 7, 2068 DOI: 10.1039/D2QM01372J

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