Evanthia Chazapi, Eftichia Kritsi, Constantinos Potamitis, Panagiota G V Liggri, Katerina E Tsitsanou, Christina E Drakou, Antonios Michaelakis, Dimitrios P Papachristos, Spyros E Zographos, Maria Zervou, Theodora Calogeropoulou
{"title":"AgamOBP1-Directed Discovery of Repellents to Control the Spread of Mosquito-Borne Diseases.","authors":"Evanthia Chazapi, Eftichia Kritsi, Constantinos Potamitis, Panagiota G V Liggri, Katerina E Tsitsanou, Christina E Drakou, Antonios Michaelakis, Dimitrios P Papachristos, Spyros E Zographos, Maria Zervou, Theodora Calogeropoulou","doi":"10.1002/cmdc.202500555","DOIUrl":null,"url":null,"abstract":"<p><p>Toward the discovery of novel efficient repellents, protein-directed dynamic combinatorial chemistry (pdDCC) coupled to saturation-transfer difference (STD) NMR spectroscopy was initially employed to identify modulators of the malaria vector Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1). A library of potential binders of AgamOBP1 (secondary amines) generated from two amines and seven aldehydes was designed aiming to enable interactions with critical amino acids at the DEET-site and to bridge the DEET- and Icaridin sIC-binding pockets, both implicated in repellents recognition. Solubility issues hindered the clear identification of binders among the DCL members, except for one sublibrary, leading us to shift our strategy towards the synthesis of the designed amines, followed by direct evaluation of their binding to AgamOBP1 using <sup>1</sup>H STD NMR spectroscopy. The identified binders were further validated in vitro by fluorescence competition assays, and the most potent compounds which also possessed suitable vapor pressure were evaluated as repellents in arm-in-cage behavioral assays against Aedes albopictus. Amines 2A, 3A, 4A, and 6A showed significant repellent activity. The most potent was compound 4A (4-methyl-N-(pyridin-4-ylmethyl)aniline) which acted as a a DEET-like repellent at 0.4 μL cm<sup>-</sup> <sup>2</sup> dose. Thus, our strategy showcased a promising scaffold for further optimization toward efficient mosquito repellents.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500555"},"PeriodicalIF":3.4000,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500555","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Toward the discovery of novel efficient repellents, protein-directed dynamic combinatorial chemistry (pdDCC) coupled to saturation-transfer difference (STD) NMR spectroscopy was initially employed to identify modulators of the malaria vector Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1). A library of potential binders of AgamOBP1 (secondary amines) generated from two amines and seven aldehydes was designed aiming to enable interactions with critical amino acids at the DEET-site and to bridge the DEET- and Icaridin sIC-binding pockets, both implicated in repellents recognition. Solubility issues hindered the clear identification of binders among the DCL members, except for one sublibrary, leading us to shift our strategy towards the synthesis of the designed amines, followed by direct evaluation of their binding to AgamOBP1 using 1H STD NMR spectroscopy. The identified binders were further validated in vitro by fluorescence competition assays, and the most potent compounds which also possessed suitable vapor pressure were evaluated as repellents in arm-in-cage behavioral assays against Aedes albopictus. Amines 2A, 3A, 4A, and 6A showed significant repellent activity. The most potent was compound 4A (4-methyl-N-(pyridin-4-ylmethyl)aniline) which acted as a a DEET-like repellent at 0.4 μL cm-2 dose. Thus, our strategy showcased a promising scaffold for further optimization toward efficient mosquito repellents.
期刊介绍:
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
Contents
ChemMedChem publishes an attractive mixture of:
Full Papers and Communications
Reviews and Minireviews
Patent Reviews
Highlights and Concepts
Book and Multimedia Reviews.