Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: September 20, 1996
Publication Date: N/A
Interpretive Summary: Neuropeptides are small chains of amino acids (the building blocks of proteins). In insects as well as other higher forms of animal life, neuropeptides act as hormones to control a wide variety of life processes such as digestion, muscular movement, excretion, etc. Because neuropeptides are so important in regulating life processes in insects, it is possible to exploit these chemicals to develop more effective methods o controlling pest insects. However, the neuropeptides themselves will not work as insecticides because they are very unstable, because they degrade easily when acted upon by enzymes in insects, and because it would be difficult and likely impossible to develop acceptable methods for their application (they do not penetrate the outside skin or cuticle of insects). This paper reviews studies that were designed to develop neuropeptide-like compounds (mimetics) that retain appropriate biological activity but that overcome the problems associated with neuropeptides themselves. We describe the 3-dimensional structures required by one peptide class to operate within the insect and utilize that information to develop mimetics that can mimic the action at greater potency than the natural peptides and that are resistant to a major process that degrades the natural peptides. We have developed a compound that, when injected into or, more importantly, applied to the suface of a target insect, may have effects on water balance and digestion that are more pronounced than even the original neuropeptides themselves. This work is very important in efforts to exploit neuropeptide technology in the development of a new class of pest insect control agents that will be more effective, more selective, and more environmentally friendly than the conventional pesticides that are currently in use.
Technical Abstract: Members of the insect kinin family of insect neuropeptides have been isolated from a diverse group of insects and have been associated with stimulation of hindgut contractions and Malpighian tubule fluid secretion, as well as inhibition of carbohydrase release in various insects. Chemical requirements within the active core of the insect kinin sequence and the C-terminal group are discussed along with the development of mimetic analogs. Spectroscopic and molecular dynamics analysis of an active restricted-conformation insect kinin analog in aqueous solution identify two distinct turn conformations in the active core pentapeptide region, the most populous featuring a cisPro in a type VI turn. Incorporation of a sterically-hindered Aib residue, compatible with turn formation in the active core, confers complete resistance to an insect endopeptidase capable of inactivating the natural insect kinins. The resulting analogs retain potent Malpighian tubule fluid secretion activity. Replacement of the phenyl ring of a critical Phe residue in the active core pentapeptide with the ball-shaped carborane moiety leads to a pseudopeptide analog with retention of diuretic activity and greatly enhanced hydrophobicity, a character important for penetration of the insect cuticle. The development of mimetic analogs with enhanced resistance to peptidase degradation can provide useful tools to neuroendocrinologists studying mechanisms by which the insect kinins operate. Disruption of peptide-regulated processes or behavior by mimetic analogs could form the basis for future pest insect management agents.