Pepducins and Other Modified Peptides

From HTS, one interesting agonist cluster against GPR81 remained after completion and evaluation of the screening cascade. We were interested in additional 

Starting points to increase the chance of successful project delivery. The expansion of literature hits and cross hybridization failed in our hands, and a subset screen of fatty acid GPCR hbraries did not reveal any additional compounds fitting the desired PD profile either. 

Most of the curves showed steep curve behavior with a top effect up to 120% that indicates complete inhibition of cAMP production and might be caused by cell toxicity. Other compounds had bell-shaped curves. 

The data is based on the pECso values of the active compounds in the respective cAMP TRF screen. 

All of this data supported a conclusion that we were looking at physicochemical compound property behavior or an unspecific assay interference property rather than specific interactions with a given receptor. It was surprising that all three assay technologies against various GPCRs showed a clear response to the compounds with exception of the antagonist screen. The conclusion was that in our hands the pepducin approach would not provide a clear rational approach to identify true hits. 

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