|Nachman, Ronald - Ron|
Submitted to: Peptides
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/27/2006
Publication Date: 1/12/2007
Citation: Nachman, R.J., Fehrentz, J., Martinez, J., Kaczmarek, K., Zabrocki, J., Coast, G.M. 2007. A C-terminal aldehyde analog of the insect kinins inhibits diuresis in the housefly. Peptides. 28:146-152. 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. Neuropeptide mimics must be designed that resist degradation by enzymes in the digestive tract and blood of pest insects and interact with the active site within agricultural or medical pests by over-activating or blocking critical, neuropeptide-regulated life functions. We report on the design and synthesis of a modified version of neuropeptides of the ‘insect kinin’ class that selectively inhibits the elimination of fluids and toxins from the housefly; an action expected to allow pesticides to reach higher internal concentrations. Smaller quantities of pesticides would then be necessary to kill a pest fly. This work represents an important milestone toward the development of practical neuropeptide-like substances that will effectively control insect pests in an environmentally friendly fashion.
Technical Abstract: The insect kinins are present in a wide variety of insects and function as potent diuretic peptides in flies. A C-terminal aldehyde insect kinin analog, Fmoc-RFFPWG-H (R-LK-CHO), demonstrates stimulation of Malpighian tubule fluid secretion in crickets, but shows inhibition of both in vitro and in vivo diuresis in the housefly. R-LK-CHO reduced the total amount of urine voided over 3h from flies injected with 1 uL of distilled water by almost 50%. The analog not only inhibits stimulation of housefly fluid secretion by the native kinin Musdo-K, but also by thapsigargin, a SERCA inhibitor, and by ionomycin, a calcium ionophore. The activity of R-LK-CHO is selective, as related C-terminal aldehyde analogs do not demonstrate an inhibitory response on housefly fluid secretion. The selective inhibitory activity of R-LK-CHO on housefly tubules represents an important lead in the development of environmentally-friendly insect management agents based on the insect kinins.