Chitinase is a Potent Insecticidal Molecular Target of Camptothecin and Its Derivatives

Abstract

Camptothecin (CPT) is a prominent molecule in natural product research because of its application prospects in medicine and agriculture. In this study, CPT and its derivatives were discovered to be competitive inhibitors of group II and group h insect chitinases, both of which are key components of insect chitinolytic systems. CPT and 7-ethyl-10-hydroxycamptothecin (SN-38) inhibited group II chitinase from Ostrinia furnacalis (OfChtII) with K i values of 5.1 and 2.0 μM, respectively. Results from tryptophan fluorescence spectroscopy, molecular docking analysis, and molecular dynamics simulations revealed that both CPT and SN-38 inhibit OfChtII-C1 by interacting with solvent-exposed tryptophan residues in a substrate-binding cleft. CPT exhibited high insecticidal activity toward the orthopteran pest Locusta migratoria, possibly because of the midgut metabolism of CPT, with only moderate activities toward lepidopteran pests. Even though SN-38 exhibited much lower insecticidal activities than CPT, it still showed higher inhibitory activity toward chitinase. This study reports a new molecular target of CPT and provides insights into molecular design of CPT-based insecticides against different kinds of pests.

Design of Inhibitors Targeting Chitin-Degrading Enzymes by Bioisostere Substitutions and Scaffold Hopping for Selective Control of Ostrinia furnacalis

“…This increases the incidence and prevalence of plant diseases. 7,8 Currently, control of O. furnacalis relies mainly on insecticides such as pyrethroids. However, resistance to these insecticides is developing rapidly, and their long-term use can lead to a number of environmental and resistance problems.…”

Discovery of Multitarget Inhibitors against Insect Chitinolytic Enzymes via Machine Learning-Based Virtual Screening

“…In our recent work, high-throughput screening (HTS) was performed on a library of 1680 natural products from TargetMol to find multitarget inhibitors of insect chitinolytic enzymes. 10 The hit compounds included a series of naphthoquinones, flavonoids, and alkaloids, of which shikonin, wogonin, and camptothecin 11 have shown significant insecticidal activities against several agricultural pests. These results suggest that multitarget inhibitors of insect chitinolytic enzymes can be identified from natural products and be promising compounds for pesticides.…”

Discovery of Rhodanine Inhibitors Targeting Of ChtI Based on the π-Stacking Effect and Aqueous Solubility

“…26 Thus, the conjugate plane plays vital roles in the chitinase activity of Of ChtI. It is worth noting that compounds with a large conjugated plane, such as TP3, FQ3, 21 dipyrido-pyrimidine derivatives, 27 piperonyl rhodanines, 23 lynamicin B, 28 camptothecin (CPT) and its derivatives, 29 normally exhibit outstanding inhibitory activity toward GH18 chitinase. 24 Although some inhibitors of Of ChtI display good inhibitory potency, the low insecticidal activity appears to hamper their practical applications.…”