A novel chemical platform based on branched piperazine‐2,5‐dione derivatives (2,5‐diketopiperazines) for creating orally available biologically active peptidomimetics has been developed. The platform includes a diketopiperazine scaffold with “built‐in” functionally active peptide fragments covalently attached via linkers. The concept was applied to two hemostimulatory drugs, the dipeptide thymogen (GluTrp) and the tripeptide stemokin (IleGluTrp). Preparation of a series of respective derivatives is described. Of the five synthesized analogues, three demonstrated high hemostimulatory activity in vivo on intact mice and on ex vivo irradiated bone marrow cells. Prospects of further development of the concept are discussed.

Peptides are low-molecular-weight substances that participate in numerous important physiological functions, such as human growth and development, stress, regulation of the emotional state, sexual behavior, and immune responses. Their mechanisms of action are based on receptor–ligand interactions, which result in highly selective effects. These properties and low toxicity enable them to be considered potent drugs. Peptide preparations became possible at the beginning of the 20th century after a method was developed for selectively synthesizing peptides; however, after synthesis of the first peptide drugs, several issues related to increasing the stability, bioavailability, half-life, and ability to move across cell membranes remain unresolved. Here, we briefly review the history of peptide production and development in the biochemical industry and outline potential areas of peptide biopharmaceutical applications and modern approaches for creating pharmaceuticals based on synthetic peptides and their analogs. We also focus on original peptide drugs and the approaches used for their development by the Russian Federation.

The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with “built-in” functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for a small peptide to be taken with a particular biological activity and to be transformed into an orally stable compound displaying the same activity. Based on this approach, various peptidomimetics exhibiting hemostimulating, hemosuppressing, and adjuvant activity were prepared. In addition, new examples of a rare phenomenon when enantiomeric molecules demonstrate reciprocal biological activity are presented. Finally, the review summarizes the evolutionary approach of the short peptide pharmaceutical development from the immunocompetent organ separation to orally active cyclopeptides and peptidomimetics.