Graphical This study presented two strategies to aid in the discovery of synthetic peptide inhibitors with anti-amyloid and antimicrobial activities for Alzheimer's disease. Four synthetic peptides were identified, including the shortest linear peptide and two cyclic peptides with simple structures. Dual-functional peptides exhibiting both anti-amyloid and antimicrobial activities have attracted attention as promising candidates for Alzheimer's disease treatment. The advantage of these peptides lies in their ability to simultaneously target both the amyloid cascade hypothesis and the microbial infection hypothesis, in contrast to single-function inhibitors. However, most of the reported dual-functional peptides to date are natural peptides, and the development of synthetic peptides in this area remains limited. In this study, we propose two strategies to aid in the discovery of synthetic dual-functional peptides. We then report four distinct synthetic dual-functional peptides identified using these strategies, with the Aβ 1–40 /Aβ 1–42 fibrillation system and common bacterial strains serving as a proof-of-concept platform. One strategy involves repurposing existing knowledge, while the other breaks from established conventions. Using the first strategy, we discovered a very short dual-functional linear peptide. With the second strategy, we identified a simple dual-functional cyclic peptide. Furthermore, by combining these two strategies, we developed a hybrid dual-functional peptide incorporating both linear and cyclic structures. We hope that our findings will contribute to the future discovery of more synthetic dual-functional peptides for treating Alzheimer's disease.
Leisheng Sun,Zonghan Jiang,Dingding Li,Yao Tian,Junqi Liu,Zhiliang Sun
Multi-drug-resistant Aeromonas hydrophila infections are becoming increasingly threatening, and the development of novel antimicrobial drugs is indispensable. Herein, we demonstrate that this novel peptide is highly active against colistin-resistant A. hydrophila strain and shows sustained killing efficacy in vivo. Mechanistic studies showed that D-Q7 interacted with phosphatidylglycerol and lipopolysaccharide in the bacterial cell membrane, with an increase in intracellular ROS as well as a decrease in ATP level, ultimately leading to cell membrane disruption and bacterial death. Importantly, our study identified gene3832 as a potential regulator of membrane permeability, which may act as a potential modulator of bacterial susceptibility to D-Q7. The role of gene3832 was further confirmed by gene knockout and complementation assays. Consistently, we observed that gene3832 was also involved in biofilm formation in the colistin-resistant A. hydrophila strain. Collectively, our study provides an effective antimicrobial strategy with potential targets for the treatment of drug-resistant A. hydrophila infection.
Currently, the absolute quantification of human transferrin (hTRF) is based on several techniques other than mass spectrometry. Although these techniques provide valuable information on protein levels and can be extremely sensitive, they often lack the specificity and reproducibility that can be provided by mass spectrometry. In this study, a liquid chromatography–tandem mass spectrometry (LC/MS/MS) based targeted proteomics assay was developed and validated for the determination of transferrin in human serum. We selected the tryptic peptide 108EDPQTFYYAVAVVK121 as the surrogate analyte for quantification and used a stable isotope-labeled synthetic peptide with this sequence as an internal standard. Sample cleanup and enrichment were achieved using solid phase extraction. The validated calibration range was from 500 to 5000 ng/mL. The intra- and inter-day precisions were less than 4.9% and 9.0%, respectively. The bias for the quality control (QC) samples was less than 5.4%. Finally, this assay was successfully applied to the quantitative analysis of transferrin in clinical samples. The obtained values were assessed by independently measuring transferrin in the same samples using a commercially available immunoturbidimetric assay. As a result, the absolute concentrations determined by the LC/MS/MS assay compared well with those obtained with the immunoturbidimetric method; however, the LC/MS/MS assay afforded more reliable transferrin values at low concentrations.
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