Antiangiogenic activity and plasma stability study of peptidomimetics containing unnatural proline analogs

Biologically active peptides are often considered as leading compounds in the drugs development process. However, the peptide bond is susceptible to enzymatic hydrolysis, thus the peptides may not be entirely stable in body fluids. One of the way to reduce this effect is to design new analogs with modified structure and properties. In general, such compounds are similar to the parent peptide sequence (to preserve biological activity), but structural changes ensure higher degradation resistance due to the enzyme failure of recognizing cleavage site

Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]