Advancement from Small Peptide Pharmaceuticals to Orally Active Piperazine-2,5-dion-Based Cyclopeptides

Abstract

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.

Keywords: cyclic peptidomimetics; drug development; immunotropic peptides; reciprocal activity peptide enantiomers.

Figure 1

The general formula of peptidomimetics platform (A) and peptidomimetic AWE18. (A) For synthesizing libraries, A and D represent biologically active pharmacophores or fragments of peptide compounds; L¹ and L² are biodegradable linkers; m and n are the numbers of CH₂ groups (ranging from 0 to 4); and R^5I and R⁵ represent possible derivatives of the pharmacophore attached to the nitrogen atoms. * Indicates that an S or R optical orientation is possible at the carbon atoms at positions 3 and 6 [50]. (B) Formula for active immuno- and hematopoiesis, stimulating cyclopeptide AWE18.

Figure 2

Comparative hemostimulated activities of Thymogen (1), Stemokin (2), and AEW18(3) [27]. * p < 0.05 vs. control mice; ** p < 0.05 vs. irradiated mice; i/p—intraperitoneal; p/o—per/os administration. The ratio of the cell colony number on the recipient spleen versus the control (in %) is shown.

Figure 3

Evolution of immunoactive peptide pharmaceuticals.