# AgamOBP1‐Directed Discovery of Repellents to Control the Spread of Mosquito‐Borne Diseases

## TL;DR

Researchers developed a new strategy to find mosquito repellents by targeting a protein involved in sensing DEET-like chemicals, identifying a promising compound that works at low doses.

## Contribution

A novel scaffold for mosquito repellents was identified using protein-directed chemistry and validated for DEET-like activity.

## Key findings

- Compound 4A showed significant repellent activity against Aedes albopictus at a low dose of 0.4 μL cm−2.
- Amines 2A, 3A, 4A, and 6A were identified as potent AgamOBP1 binders and effective repellents.
- The study demonstrated a successful strategy for designing and validating DEET-like repellents.

## 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.

Toward the discovery of novel mosquito repellents, 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. 1H STD NMR spectroscopy in the presence of AgamOBP1 enabled the identification of binders. The behavioral bioassay assessment of repellent activity highlighted 4A as a DEET‐like repellent at 0.4 μL cm‐
2 dose.© 2025 WILEY‐VCH GmbH