Insect P450 inhibitors and insecticides: challenges and opportunities

Abstract

P450 enzymes are encoded by a large number of genes in insects, often over a hundred. They play important roles in insecticide metabolism and resistance, and growing numbers of P450 enzymes are now known to catalyse important physiological reactions, such as hormone metabolism or cuticular hydrocarbon synthesis. Ways to inhibit P450 enzymes specifically or less specifically are well understood, as P450 inhibitors are found as drugs, as fungicides, as plant growth regulators and as insecticide synergists. Yet there are no P450 inhibitors as insecticides on the market. As new modes of action are constantly needed to support insecticide resistance management, P450 inhibitors should be considered because of their high potential for insect selectivity, their well-known mechanisms of action and the increasing ease of rational design and testing.

Illuminating cytochrome P450 binding: Ru(ii)-caged inhibitors of CYP17A1

“…2 Due to their prevalence, potent and selective CYP inhibitors have been aggressively pursued as chemical tools, pharmaceuticals and more recently insecticides. 3 Although many CYP inhibitors have been developed, those that can be delivered at a desired time with spatial control over CYP binding are not yet available. 4 This represents an unmet need for basic research applications, and may also provide therapeutic value because off-target inhibition of CYPs in undesired tissues leads to negative side effects in the clinic ( vide infra ).…”

Strategies for the construction of insect P450 fusion enzymes

“…Six P450 families are known in insects, five of which are not found in other organisms (CYP6, CYP9, CYP12, CYP18 and CYP28). The expression levels of P450s in insects can vary [23] and they are expressed in several tissues, such as the Malpighian tubules, fat body and midgut [24]. There is no clear phylogenetic distinction between the P450s involved in physiological homeostasis and those required for detoxification, suggesting that the function of P450s can change over evolutionary timescales [24].…”

“…These could be used to investigate the origin of pesticide resistance and to facilitate the development of new insecticides that inhibit P450s [24]. Furthermore, insect P450s could also be deployed as industrial enzymes for the production of fine chemicals and pharmaceuticals that cannot be produced economically by total chemical synthesis [31] or for the development of new processes based on bioelectrocatalysis [32].…”

Transcription factor aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator is involved in regulation of the xenobiotic tolerance‐related cytochrome P450 CYP6DA2 in Aphis gossypii Glover

“…Therefore, insects are generally believed to rely on the P450s. Members of the CYP3 clade are involved in the oxidative detoxification of furanocoumarins, alkaloids, and numerous other plant secondary metabolites and synthetic insecticides (Snyder & Glendinning, ; Feyereisen, ; Scott, ; Mao et al ., ). For example, CYP6AE14 accounts for the larval tolerance of Helicoverpa armigera to gossypol, which was verified by plant‐mediated RNA interference (RNAi) analyses (Mao et al ., ).…”