Targeting the hydrophobic region of pyroglutamate-modified amyloid-β by tyrocidine A prevents its nucleation-aggregation process and its "catalytic effect" on the Aβs aggregation.

Autor: Qin W; Department of Clinical Research, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China; Medical Innovation Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China, Chen D; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; Faculty of bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, China, Wang Y; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China, Liu Z; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China, Zhou B; School of Chinese Ethnic Medicine, Guizhou Minzu University, Guiyang, China, Bu X; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China, Wen G; Department of Clinical Research, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
Jazyk: angličtina
Zdroj: Journal of biochemical and molecular toxicology [J Biochem Mol Toxicol] 2024 Aug; Vol. 38 (8), pp. e23800.
DOI: 10.1002/jbt.23800
Abstrakt: Pyroglutamate (pE)-modified amyloid-β (Aβ) peptides play a crucial role in the development of Alzheimer's disease. pEAβ 3-42 can rapidly form oligomers that gradually elongate hydrophobic segments to form β-sheet-rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEAβ 3-42 can also catalyze the aggregation of Aβ species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEAβ 3-42 -targeting antibody donanemab, molecules that strongly bind pEAβ 3-42 and prevent its aggregation and catalytic effect on Aβs may also provide potential therapeutic options for Alzheimer's disease. Here, we demonstrate that the natural antibiotic cyclopeptide tyrocidine A (TA) not only strongly inhibits the aggregation of Aβ 1-42 as previously reported, but also interacts with the hydrophobic C-terminus and middle domain of pEAβ 3-42 to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEAβ 3-42 . Furthermore, TA can disrupt the "catalytic effect" of pEAβ 3-42 on amyloid aggregates, effectively suppressing Aβ aggregation and ultimately preventing the pathological events induced by Aβs.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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