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抗疟肽通过靶向细胞膜的机制发挥作用。

Antiplasmodial peptaibols act through membrane directed mechanisms.

机构信息

Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA.

Department of Chemistry and Biochemistry, Institute for Natural Products Applications & Research Technologies, University of Oklahoma, Norman OK 73019, USA.

出版信息

Cell Chem Biol. 2024 Feb 15;31(2):312-325.e9. doi: 10.1016/j.chembiol.2023.10.025. Epub 2023 Nov 22.

DOI:10.1016/j.chembiol.2023.10.025
PMID:37995692
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10923054/
Abstract

Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity.

摘要

我们之前的研究从真菌中鉴定出了 52 种抗疟肽。为了了解它们的抗疟作用机制，我们进行了表型分析，评估了体外耐药性的演变，并对最有效的肽 HZ NPDG-I 进行了转录组分析。我们比较了 HZ NPDG-I 和另外两种肽的杀伤作用和阶段依赖性，结果表明它们都通过超微结构分析导致消化液泡（DV）内容物丢失。HZ NPDG-I 显示 DV pH 逐渐升高，DV 膜通透性受损，并且在平面膜中再构成时能够形成离子通道。该化合物对当前临床候选药物的靶标没有交叉耐药迹象，而 3 条独立进化的抗 HZ NPDG-I 系获得了多药耐药转运蛋白 pfmdr1 的非同义突变。PfMDR1 的条件敲低对其他肽类似物表现出不同的效果，表明敏感性不同。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/99c9f4aa5f0f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/bc2d6616fa31/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/38c6b5311ded/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/8a6b20731f58/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/daea9fd5716e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/f9338d563590/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/5ab8b55f6bef/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/99ee7f78dbc3/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/99c9f4aa5f0f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/bc2d6616fa31/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/38c6b5311ded/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/8a6b20731f58/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/daea9fd5716e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/f9338d563590/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/5ab8b55f6bef/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/99ee7f78dbc3/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5a0/10993303/99c9f4aa5f0f/gr7.jpg

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