Peptide and Non-Peptide Mimetics Utilize Different Pathways for Signal Transduction

Introduction Despite the central importance of peptides as drugs such as insulin, oxytocin, calcitonin, ace inhibitors, etc., there has been a prejudice against developing peptide drugs. Instead large efforts are made to develop non-peptide small molecules (“peptide mimetics”) to replace peptides. But are they true mimetics (same SAR, same bioactivity, same toxicity profile, etc.)? This issue generally has not been addressed directly. This is especially the case when the targets for the ligands are GPCRs. When the ligands are antagonists (for receptors, enzymes, etc.) this issue is not as critical as when the ligand is an agonist for a GPCR (or growth factors, or cytokines, etc.). The issue is highly relevant because biological function will depend on activation of a particular signaling pathway, and to obtain the same bioactivity will require the same SARs. To examine this conundrum we have begun to carefully evaluate whether peptide and non-peptide mimetics utilize the same signaling pathways. We find that often they do not, which raises questions regarding drug design. Here we examine the signaling of two agonist (a peptide and a nonpeptide) ligands for the human melanocortin 4 receptor (hMC4R) utilizing molecular biological, pharmacological, biophysical, and biochemical methods and demonstrate that though both are agonists they utilize quite different signaling pathways. The implications for drug design are briefly discussed.