Rational design and discovery of novel oxalate-like derivatives as aphid-repellent candidates based on odorant-binding protein 3

Odorant-binding protein (OBP) is a potential target for developing insect repellent agents. In this study, twelve novel oxalate-like derivatives containing an isoprene chain were designed and synthesized based on the binding cavity of Acyrthosiphon pisum OBP3 (ApisOBP3). All oxalate-like derivatives showed excellent binding affinity to ApisOBP3 (K-i = 2-10 mu M) and repellent activity against A. pisum (repellent rate: 44-62 %) and Myzus persicae (M. persicae, repellent rate: 49-66 %). Moreover, these oxalate-like derivatives were accidentally found to have good binding ability to another transport protein ApisOBP7 (K-i = 4-24 mu M). Among them, compound 5b showed good stability and was identified as the most promising compound with good binding affinity to ApisOBP3 (K-i = 2.53 mu M) and ApisOBP7 (K-i = 6.00 mu M) as well as the highest repellent rate against A. pisum and M. persicae (above 60 %). The introduction of a unique oxalate skeleton in compound 5b significantly promoted its binding to ApisOBP3 by hydrophobic and electrostatic interactions, as verified by the MM/GBSA method. This study proved the feasibility of rational design of novel aphid repellent agents targeting aphid OBPs.