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Title: Agonists/Antagonists of the insect kinin and pyrokinin/PBAN neuropeptide classes as tools for rational pest control

item Nachman, Ronald

Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: 4/21/2009
Publication Date: 8/15/2009
Citation: Nachman, R.J. 2009. Agonists/antagonists of the insect kinin and pyrokinin/PBAN neuropeptide classes as tools for rational pest control. In: Ishaaya, I., Horowitz, A.R., editors. Biorational Control of Arthropod Pests: Application and Resistance Management. The Netherlands:Springer. p. 21-48.

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 insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions. Nevertheless, neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest. New, selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that interact with the active site within the agricultural or medical pest in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. This book chapter summarizes recent advances in the development of synthetic mimics of neuropeptides of the insect kinin and pyrokinin classes with enhanced biostability via novel strategies. These neuropeptide mimics have been shown to interact potently with active sites in both the yellow fever mosquito and the cattle fever tick in either a nonselective, or selective, fashion. Selectivity is an important component of successful and safe pest control methodologies. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest arthropods in an environmentally friendly fashion.

Technical Abstract: The IK and PK/PBAN insect neuropeptide classes regulate critical aspects of water balance, digestion, reproduction, defense and development in insects. These neuropeptides are nonetheless subject to degradation by peptidases in the hemolymph and gut of insects and, for the most part, lack efficient bioavailability. Structure-activity studies employing restricted-conformation analogs have led to a greater understanding of the chemical and conformational aspects of the interaction of these two neuropeptide classes with expressed arthropod receptors. In the process, several turn-mimic motifs have been identified as scaffolds for the development of mimetic agonist and antagonist neuropeptide analogs with enhanced biostability. Biostable mimetic analogs of both neuropeptide families have been developed and shown to match or exceed the in vitro and in vivo activity, disrupt normal IK or PK/PBAN neuropeptide-regulated physiological processes, feature enhanced selectivity for particular physiological processes and/or species specificity, and in some cases result in increased mortality in insects. A ‘magic bullet’ IK analog selectively targets housefly Malpighian tubules, the major organ of diuresis in insects, and leads to marked inhibition of urine release. Enhancement of bioavailability has been demonstrated in the PK/PBAN neuropeptide class and amphiphilic agonist and antagonist analogs have shown an ability to efficiently penetrate in vitro preparations of insect cuticle and foregut, as well as demonstrate potent in vivo pheromonotopic activity when administered via topical or oral routes. Promising mimetic analog leads in the development of selective agents capable of disrupting neuropeptide regulated processes have been identified that may provide interesting tools for arthropod endocrinologists and new pest insect management strategies in the future.