Evaluation of Neuroprotective and Adjuvant Activities of Diketopiperazine-Based Peptidomimetics

摘要

Oral 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-diketopi-perazines 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 deriv- atives 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 cyclopepti-des 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.