Issue 26, 2021

Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection

Abstract

Amyloid aggregation and microbial infection are considered as pathological risk factors for developing amyloid diseases, including Alzheimer's disease (AD), type II diabetes (T2D), Parkinson's disease (PD), and medullary thyroid carcinoma (MTC). Due to the multifactorial nature of amyloid diseases, single-target drugs and treatments have mostly failed to inhibit amyloid aggregation and microbial infection simultaneously, thus leading to marginal benefits for amyloid inhibition and medical treatments. Herein, we proposed and demonstrated a new “anti-amyloid and antimicrobial hypothesis” to discover two host-defense antimicrobial peptides of α-defensins containing β-rich structures (human neutrophil peptide of HNP-1 and rabbit neutrophil peptide of NP-3A), which have demonstrated multi-target, sequence-independent functions to (i) prevent the aggregation and misfolding of different amyloid proteins of amyloid-β (Aβ, associated with AD), human islet amyloid polypeptide (hIAPP, associated with T2D), and human calcitonin (hCT, associated with MTC) at sub-stoichiometric concentrations, (ii) reduce amyloid-induced cell toxicity, and (iii) retain their original antimicrobial activity upon the formation of complexes with amyloid peptides. Further structural analysis showed that the sequence-independent amyloid inhibition function of α-defensins mainly stems from their cross-interactions with amyloid proteins via β-structure interactions. The discovery of antimicrobial peptides containing β-structures to inhibit both microbial infection and amyloid aggregation greatly expands the new therapeutic potential of antimicrobial peptides as multi-target amyloid inhibitors for better understanding pathological causes and treatments of amyloid diseases.

Graphical abstract: Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection

Supplementary files

Article information

Article type
Edge Article
Submitted
25 févr. 2021
Accepted
27 mai 2021
First published
28 mai 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 9124-9139

Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection

Y. Zhang, Y. Liu, Y. Tang, D. Zhang, H. He, J. Wu and J. Zheng, Chem. Sci., 2021, 12, 9124 DOI: 10.1039/D1SC01133B

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