Agents acting at G-protein coupled receptors (GPCRs) have been the most successful targets for drug development. Every new GPCR identified is immediately examined for their potential clinical applications. Likewise all novel endogenous neuropeptides are viewed as the key to discovering and unlocking the actions of an orphan GPCR. Neuropeptides are particularly important because of their proven involvement in stress, anxiety and depression, thus providing new targets for the unmet medical needs in psychiatric disorders. The identification of novel neuropeptides that act as the endogenous ligand for orphan GPCRs has been a slow and costly process that required the purification of an unstable peptide from a brain homogenate. This process has been dramatically improved by using our newly developed computational methodology. Several putative prohormones based on species comparison and pattern recognition have been identified from either the Celera Discovery System (CDS) or public sources (GenBank). ? ? In this Phase I project, first we will confirm the existence of prohormones by identifying there ? transcripts using quantitative rtPCR and localizing their expression using in situ hybridization and Northern blots. Antibodies to the neuropeptide will be produced and used for verification of the presence of the endogenous peptide. Secondly we will characterize the novel neuropeptides for in vitro binding and electrophysiological activity in mouse brain slices. Finally, a battery of standard neurobehavioral tests will be conducted to identify the functional significance of the novel neuropeptides in vivo. The novel peptides will serve as a basis for the discovery and development of small-molecule mimetics. These studies will be carried out in the Phase II (to be proposed later), in which the GPCR for the peptides will be identified and small molecule agonists and antagonists will be developed. Our ultimate goal is to develop new therapeutics for indications in anxiety, depression, schizophrenia, or other pathological symptoms often modulated by the endogenous neuropeptide system. ? ?
| Sonmez, Kemal; Zaveri, Naunihal T; Kerman, Ilan A et al. (2009) Evolutionary sequence modeling for discovery of peptide hormones. PLoS Comput Biol 5:e1000258 |
| Xie, Xinmin; Wisor, Jonathan P; Hara, Junko et al. (2008) Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. J Clin Invest 118:2471-81 |
