Insect Neuropeptides

Peptides are essential for many biological processes, acting as hormones, neurotransmitters, enzyme substrates and inhibitors, neuromodulating agents and immunomodulators. Because peptides themselves are susceptible to degradation, exhibit poor bioavailability, poor solubility, or rapid clearance, the discovery of nonpeptide molecules that mimic or block peptide function is necessary to provide lead compounds for drug development. Finding the biologically active structure of a peptide would greatly assist the search for mimics and inhibitors. Peptides are flexible molecules, so a peptide conformation found by nuclear magnetic resonance (NMR) or X-ray crystallography need not necessarily resemble the biologically active, receptor-bound conformation. However, combining activity data from related neuropeptides and their analogs with determination of shared conformational preferences provides a rational basis for probing receptor structure and designing conformationally restricted agonists and antagonists.

We are investigating the structures of neuropeptides isolated from insects, which control diverse functions including stimulating smooth muscle contractions, pheromone biosynthesis, and diuretic activity. Fragments of these peptides, usually five to ten amino acid residues, retain full biological activity and are small enough to examine computationally. Many of these insect neuropeptides are related in sequence to mammalian peptides, suggesting there are families of peptides that span many organisms. Therefore, information about biologically active conformations determined for insect neuropeptides is likely to be relevant to related neuropeptides found in humans, which display medically important functions, such as inflammation and blood pressure.

We have also investigated the effects of protein structure on a peptide in studies on catalytic antibodies.