Identification of novel juvenile-hormone signaling activators <i>via</i> high-throughput screening with a chemical library

Abstract

S Supplementary materialJuvenile hormone (JH) is an insect-specific hormone that regulates molting and metamorphosis. Hence, JH signaling inhibitors (JHSIs) and activators (JHSAs) can be used as effective insect growth regulators (IGRs) for pest management. In our previous study, we established a high-throughput screening (HTS) system for exploration of novel JHSIs and JHSAs using a Bombyx mori cell line (BmN_JF&AR cells) and succeeded in identifying novel JHSIs from a chemical library. Here, we searched for novel JHSAs using this system. The four-step HTS yielded 10 compounds as candidate JHSAs; some of these compounds showed novel basic structures, whereas the others were composed of a 4-phenoxyphenoxymethyl skeleton, the basic structure of several existing JH analogs (pyriproxyfen and fenoxycarb). Topical application of seven compounds to B. mori larvae significantly prolonged the larval period, suggesting that the identified JHSAs may be promising IGRs targeting the JH signaling pathway.

New ways and new hopes for IGR development

“…The potential of cell-based assays for HTS approaches is emphasized. Indeed, initial attempts to identify both inhibitors 22,23) and novel activators (this issue) 24) of JH signaling have been reported.…”

“…In their contribution, Kayukawa and colleagues 24) exploit a JHRE-luciferase reporter assay based on a cell line from Bombyx mori to screen a large chemical library. The same HTS performed in an antagonistic mode has recently yielded an inhibitor of JH signaling, capable of downregulating the JH-response gene Kr-h1 and inducing precocious pupation in the silkworm larvae.…”

“…The same HTS performed in an antagonistic mode has recently yielded an inhibitor of JH signaling, capable of downregulating the JH-response gene Kr-h1 and inducing precocious pupation in the silkworm larvae. 23) Here, 10 novel activators of the JHRE reporter are presented, of which several share the 4-phenoxyphenoxymethyl structure of some existing juvenoid IGRs such as pyriproxyfen, while others have distinct chemistry, 24) consistent with the great diversity of JH receptor agonists. 25,26) When tested in final-instar Bombyx larvae, seven of the activators could delay metamorphosis although they were unable to prevent pupation and provoke an extra larval molt.…”

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

“…A large-scale high-throughput screening (HTS) has identified thousands of putative chemical agonists and antagonists of the AHR-dependent transcriptional activity. 28 Initial attempts to identify novel modulators of insect JHR signaling either through chemical HTS based on a cell line from the silkworm, Bombyx mori 29,30 or using a virtual screening approach 31 have recently been reported.…”

Neuropeptide F regulates feeding via the juvenile hormone pathway in Ostrinia furnacalis larvae

“…The last type includes plant‐derived JH active substances 26,27 . In addition, several JH‐active substances have been discovered through target‐based approaches, such as high‐throughput screening 28 and virtual screening 29 . The juvenile hormone receptor methoprene‐tolerant (MET) has been reported to act as a regulatory switch to coordinate carbohydrate metabolism and energy requirements during the reproductive cycle in A. aegypti 30 …”