Search

Peptides are low-molecular-weight substances involved in numerous physiological processes, such as growth and development of the organism, stress, regulation of the emotional state, sexual behavior, and immune responses. Most peptides act as ligands for proteins, the interaction with which leads to highly selective effects. Such properties, as well as a low toxicity, allow us to consider peptides as potential effective drugs. The preparation of peptide drugs became possible at the beginning of the 20th century after the development of a method of their selective synthesis. Despite the success of the synthesis of the first peptide drugs, many issues associated with an increase in the stability, bioavailability, half-life, and the ability to move through the cell membranes remain unresolved. The review considers the historical path of development of the synthesis and production of peptides, and discusses modern approaches to the creation of peptide drugs and their application in biopharmaceutics, including in the development of original peptide drugs in Russia. [ABSTRACT FROM AUTHOR]

Over the last decades, significant progress has been made in studying agonistic and antagonistic hematopoietic peptides. The main disadvantage of this class of peptides is their low stability with noninvasive administration methods, which limits the widespread use of hematopoiesis-regulated peptide drugs in medical practice. The aim of this work is to study novel peptidomimetics with hematopoietic activity sustained in invasive and oral administration. The activity of the leading compound cyclopeptide Cyclo-[Glu(Ile)-Glu(Trp)] (CP-88) was compared to that of the pharmaceutical preparation Stemokin in stimulating the population of committed colony-forming cells in intact and irradiated mice. CP-88 peptide increases the relative number of CD34+ cells in the blood and bone marrow, leading to expanded hematopoietic stem cells. CP-88 peptide, applied 48 h before bone marrow extraction, stimulates the population of committed colony-forming cells in the normal bone marrow by 33-37% above the normal level. In recipient mice injected with irradiated bone marrow, this peptide was restored practically to normal levels of colony-forming cells in a wide range of doses at intraperitoneal and oral administration. The toxicological results conclude that in humans, considering interspecies extrapolation, the CP-88 peptide can be practically safe with a single and course administration in doses of up to 100 μg/kg. The results of this investigation underscore the significant potential of CP-88 peptide as a hematopoiesis-regulated drug and instill optimism for its future application in medical practice.

Peptides show high promise in the targeting and intracellular delivery of next-generation biotherapeutics. The main limitation is peptides' susceptibility to proteolysis in biological systems. Numerous strategies have been developed to overcome this challenge by chemically enhancing the resistance to proteolysis. In nature, amino acids, except glycine, are found in L- and D-enantiomers. The change from one form to the other will change the primary structure of polypeptides and proteins and may affect their function and biological activity. Given the inherent chiral nature of biological systems and their high enantiomeric selectivity, there is rising interest in manipulating the chirality of polypeptides to enhance their biomolecular interactions. In this review, we discuss the first examples of up-and-down homeostasis regulation by two enantiomeric drugs: immunostimulant Thymogen (L-Glu-L-Trp) and immunosuppressor Thymodepressin (D-Glu(D-Trp)). This study shows the perspective of exploring chirality to remove the chiral wall between L- and D-biomolecules. The selected clinical result will be discussed.

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.

Vaccines are widely used worldwide to prevent and protect from various infections. A variety of modern approaches to developing prophylactic and therapeutic vaccines is growing. In almost all cases, adjuvants are necessary to obtain an effective immune response.This work investigated the possibility of using the pharmaceutical peptide drug Stemokin as an adjuvant stimulating a balanced Th1/Th2 response.A study was conducted to compare the activity of Stemokin versus the approved adjuvant Alhydrogel in a murine vaccination model with the approved VAXIGRIP® vaccine.The first proof-of-concept experimental study shows that the peptide Ile-Glu-Trp has the adjuvant vaccine properties and anti-HA IgG2a enhancing response, revealing a Th1- favoring balanced Th1/Th2 immunomodulation., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The novel chemical platform formed by the branched piperazine-2,5-dione peptide derivatives (2,5-diketopiperazines) for creating non-invasive biologically active peptidomimetics has been developed. A successful application of this approach to orally available hemostimulatory peptidomimetics was demonstrated for all-L cyclopeptide from the Glu-Trp-peptide family. In the 1980s, we have separated and characterized a number of dipeptides from the thymus homogenate. The most active peptide Glu-Trp has been studied and developed into the immunostimulating drug Thymogen. The inversion of the amino acid optical form endows the dipeptides with suppressor properties: D-Glu-D-Trp-OH and D-Glu-(D-Trp)-OH, inhibit proliferation of hemopoietic progenitors in the intact bone marrow. Based on the peptide D-Glu-(D-Trp)-OH, the new immunosuppressive drug Thymodepressin has been prepared. In this work, we applied the platform mentioned above to the design and synthesis of orally active hemosuppressive Thymodepressin® analogs. The novel data for the hemosuppressor activity of the dipeptide D-Glu(D-Trp-OH)-OH and its cyclopeptide analogs are discussed. A new example is presented of a rare phenomenon when enantiomeric molecules demonstrate reciprocal (i.e., opposite) biological activities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A series of linear peptides with the general formula H-Glu(R1)-Glu(R2)-OH was subjected to cyclization under standard conditions. Formation of respective 2,5-diketopiperazines was accompanied by transformation of the N-terminal Glu(R1) to pyroglutamic acid residue. Even in the case R1 is an amino acid residue attached to the N-terminal γ-carboxyl group, lactamization leads to its elimination. The observed reaction has not been reported so far in the literature. Correspondingly, an alternative route to Glu(R1)-Glu(R2)-containing 2,5-diketopiperazines was applied to improve the overall yields., (Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.)

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., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Intraperitoneal administration of dermorphine induces dose-dependent changes in the temperature of the body and the tail skin of rats. The character of these changes is largely determined by the ambient temperature, i.e. it depends on the initial functional state of the thermoregulation system. Pretreatment with naloxone reduces the dermorphine-induced effects on thermoregulation but does not eliminate them completely.