|Nachman, Ronald - Ron|
|Vanden broeck, Jozef|
Submitted to: Annals of the New York Academy of Sciences
Publication Type: Peer reviewed journal
Publication Acceptance Date: 11/5/1999
Publication Date: N/A
Citation: 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 such pests. The basic premise of this research is that peptides (short chains of amino acids) serve as internal messengers in insects to regulate vital functions. Peptides themselves are unsuitable for control measures due to their instability to enzymes in the circulator and digestive systems of the insect. New, selective control measures may be developed by designing mimics of these neuropeptides that actively inhibit or stimulate functions regulated by them, resulting in disruption of the internal environment of the insect. One of the important pieces of information required to design active mimics is the 3-dimensional shape adopted by the neuropeptide in its active form. In order to function in the environment without toxicity to mammals, this shape should not be the same as sequence-related peptides in mammals. We have compared the active shape of two insect peptide classes with sequence-similar peptides in mammals and found that one pair is quite similar while another (insect kinin) is quite different, indicating that mimics with pest insect control potential can be safely designed from peptides of the latter peptide class.
Technical Abstract: A comparison of solution conformations of active, restricted-conformation analogs of two sequence-similar insect/vertebrate neuropeptide family pairs shed light on the potential existence of molecular evolutionary relationships. Analogs of the locustatachykinins and the mammalian tachykinin substance P, containing a sterically hindered Aib-NMePhe/Tyr residue block, share similar low-energy turn conformations incorporating a cis peptide bond. Conversely, restricted conformation analogs of the insect kinins and the mammalian opiate peptide Tyr-W-MIF-1, with near identical C-terminal tetrapeptide sequences, adopt different conformations. The insect kinins adopt a cisPro 1-4 beta-turn, in which the Phe**1 is critical for bioactivity. Tyr-W-MIF-1 prefers a transPro 2-5 turn, and an additional N-terminal Phe severely inhibits u opiate receptor binding. Comparisons of the chemical/conformational requirements for receptor interaction are consistent with a distant evolutionary relationship betwee the insectatachykinins and tachykinins, but not between the insect kinins and Tyr-W-MIF-1. Therefore, analogs of the insect kinins with pest control potential can be readily designed to avoid mammalian interactions.