|Nachman, Ronald - Ron|
Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2009
Publication Date: 7/12/2009
Citation: Nachman, R.J., Wang, X.J., Etzkorn, F.A., Ben-Aziz, O., Davidovitch, M., Kaczmarek, K., Zabrocki, J., Strey, A.A., Pryor, N.W., Alstein, M. 2009. Evaluation of a PK/PBAN analog with an (E)-alkene, trans-Pro isostere identifies the Pro orientation for activity in four diverse pyrokinin bioassays. Peptides. 30:1254-1259. 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, these neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest, and inability to pass through the outside skin (cuticle) and/or digestive tract. We must design neuropeptide mimics that resist degradation by enzymes in the digestive tract and blood of pest insects and interact with the active site within the agricultural pest in such a way as to either over-activate or block critical, neuropeptide-regulated life functions. We report on the development of a new analog mimic of the ‘pyrokinin/PBAN’ neuropeptide class that clearly identifies the 3-D structure adopted by the natural hormones in four diverse life processes in several insect pests, including the moth Heliothis peltigera, an important agricultural pest. In insects, the ‘pyrokinins’ regulate such critical processes as reproduction, development and digestion. The work further identifies a new scaffold with which to design and develop analogs that resist degradation by enzymes. This discovery will aid in the design of neuropeptide-like compounds capable of disrupting the reproduction, development and feeding of insect pests. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest insects in an environmentally friendly fashion.
Technical Abstract: The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a multifunctional role in an array of important physiological processes in a variety of insects. An active core analog containing an (E)-alkene, transPro isosteric component was evaluated in four disparate PK/PBAN bioassays in four different insect species. These bioassays include pheromone biosynthesis in the moth Heliothis peltigera, melanization in the larval Spodoptera littoralis, pupariation acceleration in the larval fly Neobellieria bullata, and hindgut contraction in the cockroach Leucophaea maderae. The conformationally constrained analog demonstrated activity equivalent to parent PK/PBAN peptides of equal or similar length in all four PK/PBAN bioassays, and matched and/or approached the activity of peptides of natural length in three of them. In the melanization bioassay, the constrained analog exceeded the efficacy (maximal response) of the natural PBAN1-33 by a factor of 2. The results provide strong evidence for the orientation of Pro and the core conformation adopted by PK/PBAN neuropeptides during interaction with receptors associated with a range of disparate PK/PBAN bioassays. The work further identifies a scaffold with which to design mimetic PK/PBAN analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK/PBAN-regulated systems.