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Title: A NONPEPTIDAL PEPTIDOMIMETIC AGONIST OF THE INSECT FLRFAMIDE MYOSUPPRESSIN FAMILY

Author
item Nachman, Ronald
item OLENDER, ERIC - THE SCRIPPS RES INSTITUTE
item ROBERTS, VICTORIA - THE SCRIPPS RES INSTITUTE
item Holman, G
item YAMAMOTO, DAISUKE - MITSUBISHI-KASEI INST

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/27/1995
Publication Date: N/A
Citation: N/A

Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling such pests. The basic premise of this research is that peptides (short chains of amino acids) serve as internal messengers in insects to regulate vital functions. Peptides themselves are unsuitable efor control measures due to their instability to insect digestive enzymes and environmental factors. New, selective control measures may be developed by designing and/or discovering chemicals that actively inhibit or stimulate peptide regulated functions, resulting in disruption of the internal environment of the insect. We describe the first nonpeptide analog of an insect neuropeptide family. In this report, we show that the nonpeptide interacts with the same site of action, or "receptor," as the insect myosuppressin (inhibit muscle action) peptides. Modeling studies provide explanations as to how the nonpeptide could mimic an insect neuropeptide. This family of peptides includes potent inhibitors of heart and digestive tract muscles, in addition to having effects on skeletal muscle, longitudinal flight muscles, and salivary glands. This milestone discovery provides a unique opportunity to finally target an insect neuropeptide system for the development of future pest management strategies.

Technical Abstract: Benzethonium chloride (Bztc) is the first totally nonpeptide ligand for an insect, indeed an invertebrate, peptide receptor. Bztc mimics the inhibitory physiological activity of the myosuppressins, a subfamily of the FLRFamides, in three different insect bioassay systems. The inhibitory action of leucomyosuppressin and the nonpeptide Bztc in both the cockroach hindgut and the mealworm neuromuscular junction can be blocked by the lipoxygenase inhibitor, nordihydroguaiaretic acid, providing evidence for a similar mode of action. In addition, Bztc competitively displaces a radiolabeled myosuppressin analog from high and low affinity receptors of the locust oviduct. Thus, the nonpeptide interacts with both binding and activating regions of myosuppressin receptors. Molecular dynamics experiments in which selected functional groups of Bztc were fit onto corresponding functional groups of low energy myosuppressin pentapeptide structures indicate how Bztc may mimic the myosuppressins at a molecular level. The discovery of Bztc as a nonpeptidal peptidomimetic analog lead provides an opportunity to develop new pest management strategies by targeting an insect's own peptide receptor.