Hongxuan Cao, Zeyue Huang, Zheng Liu, Muhammad Salman Hameed, Jian Wan, Li Rao, Nokwanda P. Makunga, Georgi M. Dobrikov, Chen Su, Chao Peng, Yanliang Ren
{"title":"Target Fishing Reveals a Novel Mechanism of N-Acylamino Saccharin Derivatives Targeting Glyceraldehyde-3-Phosphate Dehydrogenase toward Cyanobacterial Blooms Control","authors":"Hongxuan Cao, Zeyue Huang, Zheng Liu, Muhammad Salman Hameed, Jian Wan, Li Rao, Nokwanda P. Makunga, Georgi M. Dobrikov, Chen Su, Chao Peng, Yanliang Ren","doi":"10.1021/acs.jafc.4c02651","DOIUrl":null,"url":null,"abstract":"Based on current challenges of poor targeting and limited choices in chemical control methods of cyanobacterial blooms (CBs), identifying new targets is an urgent and formidable task in the quest for target-based algaecides. This study discovered <i>N</i>-acylamino saccharin derivatives exhibiting potent algicidal activity. Thus, using <i>N</i>-acylamino saccharin as the probes, glyceraldehyde-3-phosphate dehydrogenase from cyanobacterial (<i>Cy</i>GAPDH) was identified as a new target of algaecides through the activity-based protein profiling (ABPP) strategy for the first time. Building upon the structure of <b>Probe2</b>, a series of derivatives were designed and synthesized, with compound <b>b6</b> demonstrating the most potent inhibitory activity against <i>Cy</i>GAPDH and <i>Synechocystis</i> sp. PCC6803 (IC<sub>50</sub> = 1.67 μM and EC<sub>50</sub> = 1.15 μM). Furthermore, the potential covalent binding model of <b>b6</b> to the cysteine residue C154 was explored through covalent possibility prediction, LC–MS experiments, substrate competitive inhibition experiments, and molecular docking. Especially, the results revealed C154 as a crucial covalent binding site, with residues T184 and R11 forming robust hydrophobic interactions and H181 establishing significant hydrogen-bonding interactions with <b>b6</b>, highlighting their potential as essential pharmacophores. In summary, this study not only identifies a novel target of algaecides for the control of CB but also lays the solid foundation for the development of targeted covalent algaecides.","PeriodicalId":41,"journal":{"name":"Journal of Agricultural and Food Chemistry","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Agricultural and Food Chemistry","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.1021/acs.jafc.4c02651","RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"AGRICULTURE, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Based on current challenges of poor targeting and limited choices in chemical control methods of cyanobacterial blooms (CBs), identifying new targets is an urgent and formidable task in the quest for target-based algaecides. This study discovered N-acylamino saccharin derivatives exhibiting potent algicidal activity. Thus, using N-acylamino saccharin as the probes, glyceraldehyde-3-phosphate dehydrogenase from cyanobacterial (CyGAPDH) was identified as a new target of algaecides through the activity-based protein profiling (ABPP) strategy for the first time. Building upon the structure of Probe2, a series of derivatives were designed and synthesized, with compound b6 demonstrating the most potent inhibitory activity against CyGAPDH and Synechocystis sp. PCC6803 (IC50 = 1.67 μM and EC50 = 1.15 μM). Furthermore, the potential covalent binding model of b6 to the cysteine residue C154 was explored through covalent possibility prediction, LC–MS experiments, substrate competitive inhibition experiments, and molecular docking. Especially, the results revealed C154 as a crucial covalent binding site, with residues T184 and R11 forming robust hydrophobic interactions and H181 establishing significant hydrogen-bonding interactions with b6, highlighting their potential as essential pharmacophores. In summary, this study not only identifies a novel target of algaecides for the control of CB but also lays the solid foundation for the development of targeted covalent algaecides.
期刊介绍:
The Journal of Agricultural and Food Chemistry publishes high-quality, cutting edge original research representing complete studies and research advances dealing with the chemistry and biochemistry of agriculture and food. The Journal also encourages papers with chemistry and/or biochemistry as a major component combined with biological/sensory/nutritional/toxicological evaluation related to agriculture and/or food.