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Bioactive Peptides and Proteins

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 31513

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Prof. Dr. Vadim T. Ivanov

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Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia
Interests: Author of over 400 publications dealing with synthesis, conformation, and the molecular mechanisms of biological activity of a broad variety of peptides: membrane active antibiotics, toxins, neuropeptides, immunostimulatory glycopeptides, and synthetic vaccines. Systemic study of the biodiversity of peptides. Discovery of novel endogenous peptides in animal tissues, plants, and microbial cells. Study of their biological function. Application of peptidomics to medical diagnostics.

Special Issue Information

Dear Colleagues,

Peptides and proteins directly perform or affect the majority of metabolic processes in living organisms. The rapid development of modern analytical techniques provides conditions for the systemic screening of biological samples and leads to the discovery of numerous new active molecules. Increasing numbers of peptides and proteins are considered as potential drugs and are subjected to extensive structural–functional studies. The molecular mechanisms of peptide/protein interactions with respective receptors provide another link connecting biomolecular research with medicine. This Special Issue aims to present the current trends in the intensively developing area of bioactive peptides and proteins.

Prof. Dr. Vadim T. Ivanov
Guest Editor

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Keywords

peptide/protein
synthesis
conformation
structure–activity relationship
receptors
drug design
peptidomics

Published Papers (11 papers)

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Research

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17 pages, 14718 KiB

Open AccessArticle

Thymodepressin—Unforeseen Immunosuppressor

by Vladislav I. Deigin, Yulia E. Vinogradova, Dmitry L. Vinogradov, Marina S. Krasilshchikova and Vadim T. Ivanov

Molecules 2021, 26(21), 6550; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216550 - 29 Oct 2021

Cited by 2 | Viewed by 1593

Abstract

The paper summarizes the available information concerning the biological properties and biomedical applications of Thymodepressin. This synthetic peptide drug displays pronounced immunoinhibitory activity across a wide range of conditions in vitro and in vivo. The history of its unforeseen discovery is briefly reviewed, and the current as well as potential expansion areas of medicinal practice are outlined. Additional experimental evidence is obtained, demonstrating several potential advantages of Thymodepressin over another actively used immunosuppressor drug, cyclosporin A. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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13 pages, 2207 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Desmuramyl Dipeptides Modified by Adamantyl-1,2,3-triazole

by Vesna Petrović Peroković, Željka Car, Josip Draženović, Ranko Stojković, Lidija Milković, Mariastefania Antica, Đani Škalamera, Srđanka Tomić and Rosana Ribić

Molecules 2021, 26(21), 6352; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216352 - 21 Oct 2021

Cited by 5 | Viewed by 2737

Abstract

Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment able to trigger the immune response. Structural modification of MDP can lead to the preparation of analogs with improved immunostimulant properties, including desmuramyl peptides (DMPs). The aim of this work was to prepare the desmuramyl peptide (L-Ala-D-Glu)-containing adamantyl-triazole moiety and its mannosylated derivative in order to study their immunomodulatory activities in vivo. The adjuvant activity of the prepared compounds was evaluated in a murine model using ovalbumin as an antigen, and compared to the reference adjuvant ManAdDMP. The results showed that the introduction of the lipophilic adamantyl-triazole moiety at the C-terminus of L-Ala-D-Glu contributes to the immunostimulant activity of DMP, and that mannosylation of DMP modified with adamantyl-triazole causes the amplification of its immunostimulant activity. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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14 pages, 2654 KiB

Open AccessArticle

Construction of a Tandem Repeat Peptide Sequence with Pepsin Cutting Sites to Produce Recombinant α-Melanocyte-Stimulating Hormone

by Dai-Lin Jiang, Chao-Ling Yao, Nien-Jen Hu and Yung-Chuan Liu

Molecules 2021, 26(20), 6207; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206207 - 14 Oct 2021

Cited by 1 | Viewed by 2117

Abstract

The production of α-melanocyte-stimulating hormone (α-MSH), a peptide hormone composed of 13 amino acids, is attempted by recombinant expression using E. coli as the host. To achieve this aim, a synthetic gene containing eight tandem repeats of msh gene (8msh) was designed for ribosomal synthesis of 8 α-MSH. The merit of the strategy is to diminish the peptide toxicity against the host cell and to achieve a higher production yield. Pepsin cleavage sites are introduced between the peptides for enzymatic proteolysis to obtain the monomeric peptide of α-MSH. The constructed plasmid was transformed into different strains of E. coli hosts, and E. coli XL1-Blue with gene 8msh revealed the highest yield of 8 α-MSH. Although 8 α-MSH was fractionalized in the insoluble pellets after cell lysis, pepsin cleavage was able to produce soluble α-MSH peptide, as analyzed and confirmed by mass spectrometry and peptide activity assays. The production of α-MSH was quantified using HPLC with a yield of 42.9 mg/L of LB culture. This study demonstrates the feasibility of producing α-MSH using recombinant expression of tandem repeat gene. The production procedure involves minimal post-treatment and processing and can be scaled up for industrial application. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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11 pages, 1110 KiB

Open AccessFeature PaperArticle

Delta Sleep-Inducing Peptide Recovers Motor Function in SD Rats after Focal Stroke

by Elena A. Tukhovskaya, Alina M. Ismailova, Elvira R. Shaykhutdinova, Gulsara A. Slashcheva, Igor A. Prudchenko, Inessa I. Mikhaleva, Oksana N. Khokhlova, Arkady N. Murashev and Vadim T. Ivanov

Molecules 2021, 26(17), 5173; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175173 - 26 Aug 2021

Cited by 1 | Viewed by 2456

Abstract

Background and Objectives: Mutual effect of the preliminary and therapeutic intranasal treatment of SD rats with DSIP (8 days) on the outcome of focal stroke, induced with intraluminal middle cerebral occlusion (MCAO), was investigated. Materials and Methods: The groups were the following: MCAO + vehicle, MCAO + DSIP, and SHAM-operated. DSIP or vehicle was applied nasally 60 (±15) minutes prior to the occlusion and for 7 days after reperfusion at dose 120 µg/kg. The battery of behavioral tests was performed on 1, 3, 7, 14, and 21 days after MCAO. Motor coordination and balance and bilateral asymmetry were tested. At the end of the study, animals were euthanized, and their brains were perfused, serial cryoslices were made, and infarction volume in them was calculated. Results: Although brain infarction in DSIP-treated animals was smaller than in vehicle-treated animals, the difference was not significant. However, motor performance in the rotarod test significantly recovered in DSIP-treated animals. Conclusions: Intranasal administration of DSIP in the course of 8 days leads to accelerated recovery of motor functions. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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12 pages, 1802 KiB

Open AccessArticle

PLGA Nanoparticles Decorated with Anti-HER2 Affibody for Targeted Delivery and Photoinduced Cell Death

by Victoria Olegovna Shipunova, Anna Samvelovna Sogomonyan, Ivan Vladimirovich Zelepukin, Maxim Petrovich Nikitin and Sergey Mikhailovich Deyev

Molecules 2021, 26(13), 3955; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26133955 - 28 Jun 2021

Cited by 26 | Viewed by 3888

Abstract

The effect of enhanced permeability and retention is often not sufficient for highly effective cancer therapy with nanoparticles, and the development of active targeted drug delivery systems based on nanoparticles is probably the main direction of modern cancer medicine. To meet the challenge, we developed polymer PLGA nanoparticles loaded with fluorescent photosensitive xanthene dye, Rose Bengal, and decorated with HER2-recognizing artificial scaffold protein, affibody Z_HER2:342. The obtained 170 nm PLGA nanoparticles possess both fluorescent and photosensitive properties. Namely, under irradiation with the green light of 540 nm nanoparticles, they produced reactive oxygen species leading to cancer cell death. The chemical conjugation of PLGA with anti-HER2 affibody resulted in the selective binding of nanoparticles only to HER2-overexpressing cancer cells. HER2 is a receptor tyrosine kinase that belongs to the EGFR/ERbB family and is overexpressed in 30% of breast cancers, thus serving as a clinically relevant oncomarker. However, the standard targeting molecules such as full-size antibodies possess serious drawbacks, such as high immunogenicity and the need for mammalian cell production. We believe that the developed affibody-decorated targeted photosensitive PLGA nanoparticles will provide new solutions for ongoing problems in cancer diagnostics and treatment, as well in cancer theranostics. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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14 pages, 8506 KiB

Open AccessArticle

Novel Bradykinin Receptor Inhibitors Inhibit Proliferation and Promote the Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the ERK Pathway

by Yiou Wang, Bingxue Zhang, Yibing Huang, Wenjun Yao, Fei Tao and Yuxin Chen

Molecules 2021, 26(13), 3915; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26133915 - 26 Jun 2021

Cited by 5 | Viewed by 1791

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Studies have shown that bradykinin (BK) is highly expressed in liver cancer. We designed the novel BK receptor inhibitors J051-71 and J051-105, which reduced the viability of liver cancer cells and inhibited the formation of cancer cell colonies. J051-71 and J051-105 reduced cell proliferation and induced apoptosis in HepG2 and BEL-7402 cells, which may be due to the inhibition of the extracellular regulated protein kinase (ERK) signaling pathway. In addition, these BK receptor inhibitors reversed the cell proliferation induced by BK in HepG2 and BEL-7402 cells by downregulating B1 receptor expression. Inhibiting B1 receptor expression decreased the protein levels of p-ERK and reduced the malignant progression of HCC, providing a potential target for HCC therapy. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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10 pages, 15176 KiB

Open AccessArticle

Antioxidant Fusion Protein SOD1-Tat Increases the Engraftment Efficiency of Total Bone Marrow Cells in Irradiated Mice

by Ting Bei, Xusong Cao, Yun Liu, Jinmei Li, Haihua Luo, Lin Huang, Tian Tian, Lei Li and Yong Jiang

Molecules 2021, 26(11), 3395; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26113395 - 03 Jun 2021

Cited by 1 | Viewed by 1722

Abstract

Total body irradiation is a standard procedure of bone marrow transplantation (BMT) which causes a rapid increase in reactive oxygen species (ROS) in the bone marrow microenvironment during BMT. The increase in ROS reduces the engraftment ability of donor cells, thereby affecting the bone marrow recovery of recipients after BMT. In the early weeks following transplantation, recipients are at high risk of severe infection due to weakened hematopoiesis. Thus, it is imperative to improve engraftment capacity and accelerate bone marrow recovery in BMT recipients. In this study, we constructed recombinant copper/zinc superoxide dismutase 1 (SOD1) fused with the cell-penetrating peptide (CPP), the trans-activator of transcription (Tat), and showed that this fusion protein has penetrating ability and antioxidant activity in both RAW264.7 cells and bone marrow cells in vitro. Furthermore, irradiated mice transplanted with SOD1-Tat-treated total bone marrow donor cells showed an increase in total bone marrow engraftment capacity two weeks after transplantation. This study explored an innovative method for enhancing engraftment efficiency and highlights the potential of CPP-SOD1 in ROS manipulation during BMT. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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Review

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20 pages, 961 KiB

Open AccessReview

Peptide Regulation of Gene Expression: A Systematic Review

by Vladimir Khatskelevich Khavinson, Irina Grigor’evna Popovich, Natalia Sergeevna Linkova, Ekaterina Sergeevna Mironova and Anastasiia Romanovna Ilina

Molecules 2021, 26(22), 7053; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26227053 - 22 Nov 2021

Cited by 14 | Viewed by 4174

Abstract

Peptides are characterized by their wide range of biological activity: they regulate functions of the endocrine, nervous, and immune systems. The mechanism of such action of peptides involves their ability to regulate gene expression and protein synthesis in plants, microorganisms, insects, birds, rodents, primates, and humans. Short peptides, consisting of 2–7 amino acid residues, can penetrate into the nuclei and nucleoli of cells and interact with the nucleosome, the histone proteins, and both single- and double-stranded DNA. DNA–peptide interactions, including sequence recognition in gene promoters, are important for template-directed synthetic reactions, replication, transcription, and reparation. Peptides can regulate the status of DNA methylation, which is an epigenetic mechanism for the activation or repression of genes in both the normal condition, as well as in cases of pathology and senescence. In this context, one can assume that short peptides were evolutionarily among the first signaling molecules that regulated the reactions of template-directed syntheses. This situation enhances the prospects of developing effective and safe immunoregulatory, neuroprotective, antimicrobial, antiviral, and other drugs based on short peptides. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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14 pages, 2176 KiB

Open AccessReview

Barnase-Barstar Pair: Contemporary Application in Cancer Research and Nanotechnology

by Olga Shilova, Polina Kotelnikova, Galina Proshkina, Elena Shramova and Sergey Deyev

Molecules 2021, 26(22), 6785; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226785 - 10 Nov 2021

Cited by 5 | Viewed by 2948

Abstract

Barnase is an extracellular ribonuclease secreted by Bacillus amyloliquefaciens that was originally studied as a small stable enzyme with robust folding. The identification of barnase intracellular inhibitor barstar led to the discovery of an incredibly strong protein-protein interaction. Together, barnase and barstar provide a fully genetically encoded toxin-antitoxin pair having an extremely low dissociation constant. Moreover, compared to other dimerization systems, the barnase-barstar module provides the exact one-to-one ratio of the complex components and possesses high stability of each component in a complex and high solubility in aqueous solutions without self-aggregation. The unique properties of barnase and barstar allow the application of this pair for the engineering of different variants of targeted anticancer compounds and cytotoxic supramolecular complexes. Using barnase in suicide gene therapy has also found its niche in anticancer therapy. The application of barnase and barstar in contemporary experimental cancer therapy is reflected in the review. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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29 pages, 8692 KiB

Open AccessReview

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

by Xiaoqing Ye, Jean-François Gaucher, Michel Vidal and Sylvain Broussy

Molecules 2021, 26(22), 6759; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226759 - 09 Nov 2021

Cited by 8 | Viewed by 3296

Abstract

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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21 pages, 2313 KiB

Open AccessReview

Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer’s Disease Development

by Anatoly S. Urban, Konstantin V. Pavlov, Anna V. Kamynina, Ivan S. Okhrimenko, Alexander S. Arseniev and Eduard V. Bocharov

Molecules 2021, 26(10), 2897; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26102897 - 13 May 2021

Cited by 13 | Viewed by 3731

Abstract

Alzheimer’s disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides (Aβ) triggers the disease. Aβ accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques. Aβ isoforms of different lengths are found in healthy human brains regardless of age and appear to play a role in signaling pathways in the brain and to have neuroprotective properties at low concentrations. In recent years, different substances have been developed targeting Aβ production, aggregation, interaction with other molecules, and clearance, including peptide-based drugs. Aβ is a product of sequential cleavage of the membrane glycoprotein APP (amyloid precursor protein) by β- and γ-secretases. A number of familial mutations causing an early onset of the disease have been identified in the APP, especially in its transmembrane domain. The mutations are reported to influence the production, oligomerization, and conformational behavior of Aβ peptides. This review highlights the results of structural studies of the main proteins involved in Alzheimer’s disease pathogenesis and the molecular mechanisms by which perspective therapeutic substances can affect Aβ production and nucleation. Full article

(This article belongs to the Special Issue Bioactive Peptides and Proteins)

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