Evaluation of Neuroprotective and Adjuvant Activities of Diketopiperazine‐Based Peptidomimetics

Abstract

AbstractOral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform has been developed based on branched 2,5‐diketopiperazines for creating orally active peptidomimetics. The platform includes a diketopiperazine bio‐carrier with “built‐in” functionally active peptide fragments or molecules coupled via linkers, transforming it into an orally available compound displaying the same type of activity. Based on this approach, we prepared several compounds that exhibit hemostimulating, hemosuppressing, and adjuvant activity. In this work, we screened the activity of substituted piperazine‐2,5‐dione derivatives in two experimental models: human neuroblastoma MC‐65 cells and as an adjuvant in response to ovalbumin invasion. As a result, some original cyclopeptide derivatives have demonstrated neuroprotective and adjuvant activity. The maximum neuroprotective activity was shown by cyclo‐[Glu(Ile)Glu(Trp)] and cyclo‐[AlaGlu(Trp)]; branched cyclopeptides containing a disaccharide component cyclo‐[L–Lys(N‐acetyl‐Glucosamine‐N‐acetyl‐muramyl)‐L‐Glu(L‐Trp‐OH)] and palmitic acid cyclo‐[L–Lys (Palmitoyl)‐L‐Glu(L‐Trp‐OH)] showed the highest adjuvant activity.