AgamOBP1-Directed Discovery of Repellents to Control the Spread of Mosquito-Borne Diseases.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-21 DOI:10.1002/cmdc.202500555
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
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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.

以agamobp1为导向的驱蚊剂的发现以控制蚊媒疾病的传播。
为了发现新的高效驱蚊剂,最初采用蛋白质导向动态组合化学(pdDCC)结合饱和转移差(STD)核磁共振波谱法来鉴定疟疾媒介冈比亚按蚊气味结合蛋白1 (AgamOBP1)的调节剂。由两种胺和7种醛生成的AgamOBP1(二级胺)潜在结合物库设计旨在实现与避蚊胺位点关键氨基酸的相互作用,并连接避蚊胺和伊卡苷的硅基结合口袋,两者都与驱蚊剂识别有关。溶解度问题阻碍了DCL成员之间的结合物的清晰识别,除了一个亚库,导致我们将策略转向合成设计的胺,然后使用1H STD NMR直接评估它们与AgamOBP1的结合。通过体外荧光竞争实验进一步验证了所鉴定的结合物的有效性,并在笼中对白纹伊蚊进行了驱避实验,评价了具有合适蒸气压的最有效化合物的驱避效果。胺2A、3A、4A和6A具有显著的驱避活性。化合物4A(4-甲基- n-(吡啶-4-甲基)苯胺)驱避效果最好,剂量为0.4 μL cm- 2。因此,我们的策略为进一步优化高效驱蚊剂展示了一个有前途的支架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
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.
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