|Nachman, Ronald - Ron|
|Lopez, Juan De Dios|
Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2001
Publication Date: N/A
Interpretive Summary: Because of problems with the development of resistance to conventional insecticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. Neuropeptides are short chains of amino acids that serve as potent internal messengers in insects to regulate vital functions. Neuropeptides are unsuitable for use in control measures because they degrade in the circulatory and digestive systems, and an inability to penetrate the outer surface of the insect. Selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that actively inhibit or over-stimulate functions regulated by them, resulting in disruption of the internal environment of the insect. We identify portions of the selected neuropeptide that are susceptible to degradation in the circulatory and digestive systems, and design and synthesize mimics with greatly enhanced stability. The mimics are shown to remain within the insect for long periods and demonstrate enhanced biological activity, including a pronounced inhibition of weight gain in the destructive larvae of the corn earworm. This information is critical to efforts to produce control measures that can selectively disrupt insect life processes. This work leads us one step closer to the development of practical neuropeptide mimics that will effectively control certain pests in an environmentally friendly fashion.
Technical Abstract: The diuretic/myotropic insect kinin neuropeptides, which share the common C-terminal pentapeptide core FX1X2WG-NH2, reveal primary (X2-W) and secondary (N-terminal to F) sites of susceptibility to peptidases bound to corn earworm (H. zea) Malpighian tubule tissue. Analogs designed to enhance resistance to tissue-bound peptidases, and pure insect neprilysin and ACE, demonstrate markedly enhanced in vivo activity in a weight gain inhibition assay in H. zea, and strong in vivo diuretic activity in the housefly (M. domestica). The peptidase-resistant insect kinin analog pQK(pQ)FF[Aib]WB-NH2 demonstrates a longer internal residence time in the housefly than the native muscakinin (MK), and despite a difference of over four orders of magnitude in an in vitro Malpighian tubule fluid secretion assay, is equipotent with MP in an in vivo housefly diuretic assay. Aminohexanoic acid (Ahx) is shown to function as a surrogate for N- terminal Lys, while at the same time providing enhanced resistance to aminopeptidase attack. Peptidaese-resistant insect kinin analogs demonstrate enhanced inhibition of weight gain in larvae of the agriculturally destructive corn earworm moth. Potent peptidase resistant analogs of the insect kinins, coupled with an increased understanding of related regulatory factors, offer promise in the development of new, environmentally friendly pest insect control measures.