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Title: Potent activity of a PK/PBAN analog with an (E)-alkene, trans-Pro mimic identifies the Pro orientation and core conformation during interaction with HevPBANR-C receptor

Author
item Nachman, Ronald
item KIM, YOUNG-JOON - UNIV OF CA, RIVERSIDE
item WANG, XIAODONG - VA TECH UNIV
item ETZKORN, FELICIA - VA TECH UNIV
item KACZMAREK, KRZYSZTOF - TECHNICAL UNIV, POLAND
item ZABROCKI, JANUSZ - TECHNICAL UNIV, POLAND
item ADAMS, MICHAEL - UNIV OF CA, RIVERSIDE

Submitted to: Bioorganic and Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2009
Publication Date: 6/15/2009
Citation: Nachman, R.J., Kim, Y., Wang, X.J., Etzkorn, F.A., Kaczmarek, K., Zabrocki, J., Adams, M.E. 2009. Potent activity of a PK/PBAN analog with an (E)-alkene, trans-Pro mimic identifies the Pro orientation and core conformation during interaction with HevPBANR-C receptor. Bioorganic and Medicinal Chemistry. 17:4216-4220.

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 at the active site from the moth Heliothis virescens, an important agricultural pest. In moths, PBAN regulates the release of sex pheromones, critical for reproduction. The work further identifies a new scaffold with which to design and develop analogs with enhanced biostability. This discovery will aid in the design of neuropeptide-like compounds capable of disrupting the reproduction and propagation of these and related moths. 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 insects, including regulation of sex pheromone biosynthesis in moths. A cyclic PK/PBAN analog (cyclo[NTSFTPRL]) retains significant activity on the pheromonotropic HevPBANR receptor from the tobacco budworm Heliothis virescens expressed in CHO-K1 cells. Previous studies indicate that this rigid, cyclic analog adopts a type I beta-turn with a transPro over residues TPRL within the core PK/PBAN region. An analog containing an (E)-alkene, trans-Pro mimetic motif was synthesized, and upon evaluation on the HevPBANR receptor found to have an EC50 value that is not statistically different than a parent C-terminal PK/PBAN hexapeptide sequence. The results, in aggregate, provide strong evidence for the orientation of Pro and the core conformation of PK/PBAN neuropeptides during interaction with the expressed PBAN receptor. The work further identifies a novel scaffold with which to design mimetic PBAN analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK/PBAN-regulated pheromone signaling systems.