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Fig. 2. Evolutionary diversity of proenkephalin-derived heptapeptides (the vertebrate evolutionarychart is adapted from [2]).Each novel heptapeptide was subjected to functionality studies, using receptor binding andG-protein activation assays. The relative affinities of the heptapeptides reveal rather mureceptorpreference over the delta-receptors (Figure 1/A,B,C). [ 35 S]GTPgS assay hasdemonstrated that these novel hepta-peptides are also potent in stimulating the regulatoryG-proteins (Figure 1/D).The overall binding and signaling profile of the novel heptapeptides revealed moderateopioid agonist activities and a rank order of potencies for the mu>delta>>>kappa receptorbinding sites. Importantly, these new endogenous sequences represent further illustration ofthe chemical biodiversity observed within the opioid peptide family. One significance ofthese mutationally variable sequences is that they represent a natural “combinatorial”peptide library emerged by the evolution and offer template sequences for structure-activityrelationship studies (Figure 2). Opioid peptide variability is a good example for thechemical biodiversity.AcknowledgmentsThis work was supported by grants from the National Office for Research and Technology, Hungary(OTKA-NKTH CK-78566) and by the “Foundation for Hungarian Peptide- and Protein Research”,Budapest, Hungary.References1. Bojnik, E., Babos, F., Magyar, A., Borsodi, A., Benyhe, S. Neuroscience 165(2), 542-552 (2010).2. Dores, R.M., Lecaude, S., Bauer, D., Danielson, P.B. Mass Spectrom. Rev. 21, 21-24 (2002).425