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6 pages, 204 KiB

Open AccessEditorial

Advances in Research of Short Peptides

by Joanna Bojarska

Molecules 2022, 27(8), 2446; https://doi.org/10.3390/molecules27082446 - 11 Apr 2022

Cited by 4 | Viewed by 2330

Abstract

Short peptides are unique biomolecules, which combine the advantages of classical small molecules and mature proteins and have attracted increasing interest due to their wide range of applications [...] Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

Research

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14 pages, 4835 KiB

Open AccessArticle

Bruch’s-Mimetic Nanofibrous Membranes Functionalized with the Integrin-Binding Peptides as a Promising Approach for Human Retinal Pigment Epithelium Cell Transplantation

by Shaocheng Wang, Siyong Lin, Bo Xue, Chenyu Wang, Nana Yan, Yueyan Guan, Yuntao Hu and Xuejun Wen

Molecules 2022, 27(4), 1429; https://doi.org/10.3390/molecules27041429 - 21 Feb 2022

Cited by 5 | Viewed by 2493

Abstract

Background: This study aimed to develop an ultrathin nanofibrous membrane able to, firstly, mimic the natural fibrous architecture of human Bruch’s membrane (BM) and, secondly, promote survival of retinal pigment epithelial (RPE) cells after surface functionalization of fibrous membranes. Methods: Integrin-binding peptides (IBPs) [...] Read more.

Background: This study aimed to develop an ultrathin nanofibrous membrane able to, firstly, mimic the natural fibrous architecture of human Bruch’s membrane (BM) and, secondly, promote survival of retinal pigment epithelial (RPE) cells after surface functionalization of fibrous membranes. Methods: Integrin-binding peptides (IBPs) that specifically interact with appropriate adhesion receptors on RPEs were immobilized on Bruch’s-mimetic membranes to promote coverage of RPEs. Surface morphologies, Fourier-transform infrared spectroscopy spectra, contact angle analysis, Alamar Blue assay, live/dead assay, immunofluorescence staining, and scanning electron microscopy were used to evaluate the outcome. Results: Results showed that coated membranes maintained the original morphology of nanofibers. After coating with IBPs, the water contact angle of the membrane surfaces varied from 92.38 ± 0.67 degrees to 20.16 ± 0.81 degrees. RPE cells seeded on IBP-coated membranes showed the highest viability at all time points (Day 1, p < 0.05; Day 3, p < 0.01; Days 7 and 14, p < 0.001). The proliferation rate of RPE cells on uncoated poly(ε-caprolactone) (PCL) membranes was significantly lower than that of IBP-coated membranes (p < 0.001). SEM images showed a well-organized hexa/polygonal monolayer of RPE cells on IBP-coated membranes. RPE cells proliferated rapidly, contacted, and became confluent. RPE cells formed a tight adhesion with nanofibers under high-magnification SEM. Our findings confirmed that the IBP-coated PCL membrane improved the attachment, proliferation, and viability of RPE cells. In addition, in this study, we used serum-free culture for RPE cells and short IBPs without immunogenicity to prevent graft rejection and immunogenicity during transplantation. Conclusions: These results indicated that the biomimic BM-IBP-RPE nanofibrous graft might be a new, practicable approach to increase the success rate of RPE cell transplantation. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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15 pages, 1413 KiB

Open AccessArticle

Delivery of the VIVIT Peptide to Human Glioma Cells to Interfere with Calcineurin-NFAT Signaling

by Aleksandra Ellert-Miklaszewska, Agata Szymczyk, Katarzyna Poleszak and Bozena Kaminska

Molecules 2021, 26(16), 4785; https://doi.org/10.3390/molecules26164785 - 7 Aug 2021

Cited by 7 | Viewed by 2470

Abstract

The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary [...] Read more.

The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary brain tumor, gliomas. In the present study, we demonstrate the expression of NFATs and NFAT-driven transcription in several human glioma cells. We used a VIVIT peptide for interference in calcineurin binding to NFAT via a conserved PxIxIT motif. VIVIT was expressed as a fusion protein with a green fluorescent protein (VIVIT-GFP) or conjugated to cell-penetrating peptides (CPP), Sim-2 or 11R. We analyzed the NFAT expression, phosphorylation, subcellular localization and their transcriptional activity in cells treated with peptides. Overexpression of VIVIT-GFP decreased the NFAT-driven activity and inhibited the transcription of endogenous NFAT-target genes. These effects were not reproduced with synthetic peptides: Sim2-VIVIT did not show any activity, and 11R-VIVIT did not inhibit NFAT signaling in glioma cells. The presence of two calcineurin docking sites in NFATc3 might require dual-specificity blocking peptides. The cell-penetrating peptides Sim-2 or 11R linked to VIVIT did not improve its action making it unsuitable for evaluating NFAT dependent events in glioma cells with high expression of NFATc3. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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9 pages, 1037 KiB

Open AccessCommunication

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond

by Krzysztof Kaczmarek, Barbara Pacholczyk-Sienicka, Łukasz Albrecht, Janusz Zabrocki and Ronald J. Nachman

Molecules 2021, 26(11), 3271; https://doi.org/10.3390/molecules26113271 - 28 May 2021

Cited by 4 | Viewed by 2151

Abstract

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction [...] Read more.

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap). Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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9 pages, 3111 KiB

Open AccessArticle

Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

by Norbert Odolczyk, Ewa Marzec, Maria Winiewska-Szajewska, Jarosław Poznański and Piotr Zielenkiewicz

Molecules 2021, 26(8), 2157; https://doi.org/10.3390/molecules26082157 - 9 Apr 2021

Cited by 23 | Viewed by 4343

Abstract

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases [...] Read more.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases reported to the beginning of December 2020, including over 1.5 million deaths. Unfortunately, currently, there is no specific and effective treatment for COVID-19. As SARS-CoV-2 relies on its spike proteins (S) to bind to a host cell-surface receptor angiotensin-converting enzyme-2(ACE2), and this interaction is proved to be responsible for entering a virus into host cells, it makes an ideal target for antiviral drug development. In this work, we design three very short peptides based on the ACE2 sequence/structure fragments, which may effectively bind to the receptor-binding domain (RBD) of S protein and may, in turn, disrupt the important virus-host protein–protein interactions, blocking early steps of SARS-CoV-2 infection. Two of our peptides bind to virus protein with affinity in nanomolar range, and as very short peptides have great potential for drug development. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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10 pages, 1816 KiB

Open AccessArticle

Anti-Cancer Effects of Carnosine—A Dipeptide Molecule

by Monica D. Prakash, Sarah Fraser, Jennifer C. Boer, Magdalena Plebanski, Barbora de Courten and Vasso Apostolopoulos

Molecules 2021, 26(6), 1644; https://doi.org/10.3390/molecules26061644 - 16 Mar 2021

Cited by 23 | Viewed by 4845

Abstract

Background: Carnosine is a dipeptide molecule (β-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties. Methods: In this [...] Read more.

Background: Carnosine is a dipeptide molecule (β-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties. Methods: In this study, we investigated the effect of carnosine on breast, ovarian, colon, and leukemic cancer cell proliferation. We further examined U937 promonocytic, human myeloid leukemia cell phenotype, gene expression, and cytokine secretion to determine if these are linked to carnosine’s anti-proliferative properties. Results: Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. Conclusion: These effects may have implications for a role for carnosine in anti-cancer therapy. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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9 pages, 2413 KiB

Open AccessArticle

The Wound Healing Peptide, AES16-2M, Ameliorates Atopic Dermatitis In Vivo

by Myun Soo Kim, Jisun Song, Sunyoung Park, Tae Sung Kim, Hyun Jeong Park and Daeho Cho

Molecules 2021, 26(4), 1168; https://doi.org/10.3390/molecules26041168 - 22 Feb 2021

Cited by 8 | Viewed by 2962

Abstract

Peptide materials have recently been considered for use in various industrial fields. Because of their efficacy, safety, and low cost, therapeutic peptides are studied for various diseases, including atopic dermatitis (AD). AD is a common inflammatory skin disease impairing the patient’s quality of [...] Read more.

Peptide materials have recently been considered for use in various industrial fields. Because of their efficacy, safety, and low cost, therapeutic peptides are studied for various diseases, including atopic dermatitis (AD). AD is a common inflammatory skin disease impairing the patient’s quality of life. Various therapies, such as treatments with corticosteroids, calcineurin inhibitors, and antibody drugs, have been applied, but numerous side effects have been reported, including skin atrophy, burning, and infection. In the case of antibody drugs, immunogenicity against the drugs can be a problem. To overcome these side effects, small peptides are considered therapeutic agents. We previously identified the small wound healing peptide AES16-2M with a sequence of REGRT, and examined its effects on AD in this study. Interestingly, the administration of AES16-2M downregulated the AD disease score, ear thickness, serum IgE, and thymic stromal lymphopoietin (TSLP) in AD mice. The thickness of the epidermal layer was also improved by AES16-2M treatment. In addition, quantities of IL-4-, IL-13-, and IL-17-producing CD4 T cells from peripheral lymph nodes and spleens were reduced by injection of AES16-2M. Furthermore, the expression of TSLP was significantly reduced in AES16-2M-treated human keratinocytes. Therefore, these results suggest that AES16-2M can be a novel candidate for AD treatment. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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22 pages, 6299 KiB

Open AccessArticle

Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile

by Adam Mieczkowski, Elżbieta Speina, Damian Trzybiński, Maria Winiewska-Szajewska, Patrycja Wińska, Ewelina M. Borsuk, Małgorzata Podsiadła-Białoskórska, Tomasz Przygodzki, Krzysztof Drabikowski, Lidia Stanczyk, Igor Zhukov, Cezary Watala and Krzysztof Woźniak

Molecules 2021, 26(4), 794; https://doi.org/10.3390/molecules26040794 - 3 Feb 2021

Cited by 11 | Viewed by 4390

Abstract

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues [...] Read more.

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor—tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 μM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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15 pages, 1462 KiB

Open AccessArticle

Proposal of the Annotation of Phosphorylated Amino Acids and Peptides Using Biological and Chemical Codes

by Piotr Minkiewicz, Małgorzata Darewicz, Anna Iwaniak and Marta Turło

Molecules 2021, 26(3), 712; https://doi.org/10.3390/molecules26030712 - 29 Jan 2021

Cited by 4 | Viewed by 3228

Abstract

Phosphorylation represents one of the most important modifications of amino acids, peptides, and proteins. By modifying the latter, it is useful in improving the functional properties of foods. Although all these substances are broadly annotated in internet databases, there is no unified code [...] Read more.

Phosphorylation represents one of the most important modifications of amino acids, peptides, and proteins. By modifying the latter, it is useful in improving the functional properties of foods. Although all these substances are broadly annotated in internet databases, there is no unified code for their annotation. The present publication aims to describe a simple code for the annotation of phosphopeptide sequences. The proposed code describes the location of phosphate residues in amino acid side chains (including new rules of atom numbering in amino acids) and the diversity of phosphate residues (e.g., di- and triphosphate residues and phosphate amidation). This article also includes translating the proposed biological code into SMILES, being the most commonly used chemical code. Finally, it discusses possible errors associated with applying the proposed code and in the resulting SMILES representations of phosphopeptides. The proposed code can be extended to describe other modifications in the future. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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11 pages, 1689 KiB

Open AccessArticle

Anti-Inflammatory Effect of Homo- and Heterodimers of Natural Enkephalinase Inhibitors in Experimental Colitis in Mice

by Małgorzata Sobocińska, Maciej Salaga, Jakub Fichna and Elżbieta Kamysz

Molecules 2020, 25(24), 5820; https://doi.org/10.3390/molecules25245820 - 10 Dec 2020

Cited by 7 | Viewed by 2120

Abstract

Background: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. Method: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and [...] Read more.

Background: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. Method: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. Results: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. Conclusion: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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20 pages, 2626 KiB

Open AccessArticle

In Silico Discovery of Antimicrobial Peptides as an Alternative to Control SARS-CoV-2

by Yamil Liscano, Jose Oñate-Garzón and Iván Darío Ocampo-Ibáñez

Molecules 2020, 25(23), 5535; https://doi.org/10.3390/molecules25235535 - 25 Nov 2020

Cited by 22 | Viewed by 4653

Abstract

A serious pandemic has been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The interaction between spike surface viral protein (Sgp) and the angiotensin-converting enzyme 2 (ACE2) cellular receptor is essential to understand the SARS-CoV-2 infectivity and pathogenicity. Currently, no drugs [...] Read more.

A serious pandemic has been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The interaction between spike surface viral protein (Sgp) and the angiotensin-converting enzyme 2 (ACE2) cellular receptor is essential to understand the SARS-CoV-2 infectivity and pathogenicity. Currently, no drugs are available to treat the infection caused by this coronavirus and the use of antimicrobial peptides (AMPs) may be a promising alternative therapeutic strategy to control SARS-CoV-2. In this study, we investigated the in silico interaction of AMPs with viral structural proteins and host cell receptors. We screened the antimicrobial peptide database (APD3) and selected 15 peptides based on their physicochemical and antiviral properties. The interactions of AMPs with Sgp and ACE2 were performed by docking analysis. The results revealed that two amphibian AMPs, caerin 1.6 and caerin 1.10, had the highest affinity for Sgp proteins while interaction with the ACE2 receptor was reduced. The effective AMPs interacted particularly with Arg995 located in the S2 subunits of Sgp, which is key subunit that plays an essential role in viral fusion and entry into the host cell through ACE2. Given these computational findings, new potentially effective AMPs with antiviral properties for SARS-CoV-2 were identified, but they need experimental validation for their therapeutic effectiveness. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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9 pages, 1333 KiB

Open AccessCommunication

Impact of C-Terminal Chemistry on Self-Assembled Morphology of Guanosine Containing Nucleopeptides

by Katherine Boback, Katherine Bacchi, Sarah O’Neill, Samantha Brown, Jovelt Dorsainvil and Jillian E. Smith-Carpenter

Molecules 2020, 25(23), 5493; https://doi.org/10.3390/molecules25235493 - 24 Nov 2020

Cited by 10 | Viewed by 2893

Abstract

Herein, we report the design and characterization of guanosine-containing self-assembling nucleopeptides that form nanosheets and nanofibers. Through spectroscopy and microscopy analysis, we propose that the peptide component of the nucleopeptide drives the assembly into β-sheet structures with hydrogen-bonded guanosine forming additional secondary structures [...] Read more.

Herein, we report the design and characterization of guanosine-containing self-assembling nucleopeptides that form nanosheets and nanofibers. Through spectroscopy and microscopy analysis, we propose that the peptide component of the nucleopeptide drives the assembly into β-sheet structures with hydrogen-bonded guanosine forming additional secondary structures cooperatively within the peptide framework. Interestingly, the distinct supramolecular morphologies are driven not by metal cation responsiveness common to guanine-based materials, but by the C-terminal peptide chemistry. This work highlights the structural diversity of self-assembling nucleopeptides and will help advance the development of applications for these supramolecular guanosine-containing nucleopeptides. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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11 pages, 490 KiB

Open AccessArticle

A Geometric Definition of Short to Medium Range Hydrogen-Mediated Interactions in Proteins

by Matthew Merski, Jakub Skrzeczkowski, Jennifer K. Roth and Maria W. Górna

Molecules 2020, 25(22), 5326; https://doi.org/10.3390/molecules25225326 - 15 Nov 2020

Cited by 8 | Viewed by 3232

Abstract

We present a method to rapidly identify hydrogen-mediated interactions in proteins (e.g., hydrogen bonds, hydrogen bonds, water-mediated hydrogen bonds, salt bridges, and aromatic π-hydrogen interactions) through heavy atom geometry alone, that is, without needing to explicitly determine hydrogen atom positions using either experimental [...] Read more.

We present a method to rapidly identify hydrogen-mediated interactions in proteins (e.g., hydrogen bonds, hydrogen bonds, water-mediated hydrogen bonds, salt bridges, and aromatic π-hydrogen interactions) through heavy atom geometry alone, that is, without needing to explicitly determine hydrogen atom positions using either experimental or theoretical methods. By including specific real (or virtual) partner atoms as defined by the atom type of both the donor and acceptor heavy atoms, a set of unique angles can be rapidly calculated. By comparing the distance between the donor and the acceptor and these unique angles to the statistical preferences observed in the Protein Data Bank (PDB), we were able to identify a set of conserved geometries (15 for donor atoms and 7 for acceptor atoms) for hydrogen-mediated interactions in proteins. This set of identified interactions includes every polar atom type present in the Protein Data Bank except OE1 (glutamate/glutamine sidechain) and a clear geometric preference for the methionine sulfur atom (SD) to act as a hydrogen bond acceptor. This method could be readily applied to protein design efforts. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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18 pages, 2352 KiB

Open AccessArticle

Antibacterial Activity of a Cationic Antimicrobial Peptide against Multidrug-Resistant Gram-Negative Clinical Isolates and Their Potential Molecular Targets

by Sandra Patricia Rivera-Sánchez, Helen Astrid Agudelo-Góngora, José Oñate-Garzón, Liliana Janeth Flórez-Elvira, Adriana Correa, Paola Andrea Londoño, Juan David Londoño-Mosquera, Alberto Aragón-Muriel, Dorian Polo-Cerón and Iván Darío Ocampo-Ibáñez

Molecules 2020, 25(21), 5035; https://doi.org/10.3390/molecules25215035 - 30 Oct 2020

Cited by 13 | Viewed by 3574

Abstract

Antimicrobial resistance reduces the efficacy of antibiotics. Infections caused by multidrug-resistant (MDR), Gram-negative bacterial strains, such as Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), are a serious threat to global health. However, cationic antimicrobial peptides (CAMPs) are promising as an alternative therapeutic strategy [...] Read more.

Antimicrobial resistance reduces the efficacy of antibiotics. Infections caused by multidrug-resistant (MDR), Gram-negative bacterial strains, such as Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), are a serious threat to global health. However, cationic antimicrobial peptides (CAMPs) are promising as an alternative therapeutic strategy against MDR strains. In this study, the inhibitory activity of a cationic peptide, derived from cecropin D-like (ΔM2), against MDRKp and MDRPa clinical isolates, and its interaction with membrane models and bacterial genomic DNA were evaluated. In vitro antibacterial activity was determined using the broth microdilution test, whereas interactions with lipids and DNA were studied by differential scanning calorimetry and electronic absorption, respectively. A strong bactericidal effect of ΔM2 against MDR strains, with minimal inhibitory concentration (MIC) and minimal bactericidal concentrations (MBC) between 4 and 16 μg/mL, was observed. The peptide had a pronounced effect on the thermotropic behavior of the 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG) membrane models that mimic bacterial membranes. Finally, the interaction between the peptide and genomic DNA (gDNA) showed a hyperchromic effect, which indicates that ΔM2 can denature bacterial DNA strands via the grooves. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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18 pages, 2331 KiB

Open AccessArticle

Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

by Atsushi Ueda, Mei Higuchi, Kazuki Sato, Tomohiro Umeno and Masakazu Tanaka

Molecules 2020, 25(20), 4667; https://doi.org/10.3390/molecules25204667 - 13 Oct 2020

Cited by 6 | Viewed by 2379

Abstract

We designed and synthesized helical short oligopeptides with an l-proline on the N-terminus and hydrocarbon stapling on the side chain. Side-chain stapling is a frequently used method for the development of biologically active peptides. Side-chain stapling can stabilize the secondary structures of [...] Read more.

We designed and synthesized helical short oligopeptides with an l-proline on the N-terminus and hydrocarbon stapling on the side chain. Side-chain stapling is a frequently used method for the development of biologically active peptides. Side-chain stapling can stabilize the secondary structures of peptides, and, therefore, stapled peptides may be applicable to peptide-based organocatalysts. Olefin-tethered cis-4-hydroxy-l-proline 1 and l-serine 2 and 8, and (R)-α-allyl-proline 18 were used as cross-linking motifs and incorporated into helical peptide sequences. The Z- and E-selectivities were observed for the ring-closing metathesis reactions of peptides 3 and 11 (i,i+1 series), respectively, while no E/Z-selectivity was observed for that of 19 (i,i+3 series). The stapled peptide B’ catalyzed the Michael addition reaction of 1-methylindole to α,β-unsaturated aldehyde, which was seven times faster than that of unstapled peptide B. Furthermore, the high catalytic activity was retained even at lower catalyst loadings (5 mol %) and lower temperatures (0 °C). The circular dichroism spectra of stapled peptide B’ showed a right-handed helix with a higher intensity than that of unstapled peptide B. These results indicate that the introduction of side-chain stapling is beneficial for enhancing the catalytic activity of short oligopeptide catalysts. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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9 pages, 1942 KiB

Open AccessArticle

The Reactions of H₂O₂ and GSNO with the Zinc Finger Motif of XPA. Not A Regulatory Mechanism, But No Synergy with Cadmium Toxicity

by Aleksandra Witkiewicz-Kucharczyk, Wojciech Goch, Jacek Olędzki, Andrea Hartwig and Wojciech Bal

Molecules 2020, 25(18), 4177; https://doi.org/10.3390/molecules25184177 - 12 Sep 2020

Cited by 6 | Viewed by 2532

Abstract

Tetrathiolate zinc fingers are potential targets of oxidative assault under cellular stress conditions. We used the synthetic 37-residue peptide representing the tetrathiolate zinc finger domain of the DNA repair protein XPA, acetyl-DYVICEECGKEFMSYLMNHFDLPTCDNCRDADDKHK-amide (XPAzf) as a working model to study the reaction of its [...] Read more.

Tetrathiolate zinc fingers are potential targets of oxidative assault under cellular stress conditions. We used the synthetic 37-residue peptide representing the tetrathiolate zinc finger domain of the DNA repair protein XPA, acetyl-DYVICEECGKEFMSYLMNHFDLPTCDNCRDADDKHK-amide (XPAzf) as a working model to study the reaction of its Zn(II) complex (ZnXPAzf) with hydrogen peroxide and S-nitrosoglutathione (GSNO), as oxidative and nitrosative stress agents, respectively. We also used the Cd(II) substituted XPAzf (CdXPAzf) to assess the situation of cadmium assault, which is accompanied by oxidative stress. Using electrospray mass spectrometry (ESI-MS), HPLC, and UV-vis and circular dichroism spectroscopies we demonstrated that even very low levels of H₂O₂ and GSNO invariably cause irreversible thiol oxidation and concomitant Zn(II) release from ZnXPAzf. In contrast, CdXPAzf was more resistant to oxidation, demonstrating the absence of synergy between cadmium and oxidative stresses. Our results indicate that GSNO cannot act as a reversible modifier of XPA, and rather has a deleterious effect on DNA repair. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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21 pages, 4681 KiB

Open AccessArticle

Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus

by Jolanta Dyniewicz, Piotr F. J. Lipiński, Piotr Kosson, Marta Bochyńska-Czyż, Joanna Matalińska and Aleksandra Misicka

Molecules 2020, 25(15), 3429; https://doi.org/10.3390/molecules25153429 - 28 Jul 2020

Cited by 13 | Viewed by 2905

Abstract

In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either N-acylhydrazone (NAH) or N′-acylhydrazide [...] Read more.

In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either N-acylhydrazone (NAH) or N′-acylhydrazide motifs combined with the 3,5-bis(trifluoromethyl)phenyl moiety. Eleven novel compounds were synthesized and subject to biological evaluation. The analyzed compounds exhibit a diversified range of affinities for the µ opioid receptor (MOR), rather low δ opioid receptor (DOR) affinities, and no appreciable neurokinin-1 receptor binding. In three out of four pairs, N-acylhydrazone-based derivatives bind MOR better than their N’-acylhydrazide counterparts. The best of the novel derivatives have similar low nanomolar MOR binding affinity as the reference opioids, such as morphine and biphalin. The obtained order of MOR affinities was compared to the results of molecular docking. In vivo, four tested compounds turned out to be relatively strong analgesics. Finally, the NAH-based analogues reduce the number of melanoma cells in cell culture, while their N′-acylhydrazide counterparts do not. The antimelanoma properties are roughly correlated to the lipophilicity of the compounds. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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Review

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8 pages, 652 KiB

Open AccessReview

Effects of Modifications on the Immunosuppressive Properties of Cyclolinopeptide A and Its Analogs in Animal Experimental Models

by Michał Zimecki and Krzysztof Kaczmarek

Molecules 2021, 26(9), 2538; https://doi.org/10.3390/molecules26092538 - 27 Apr 2021

Cited by 9 | Viewed by 2193

Abstract

The consequences of manipulations in structure and amino acid composition of native cyclolinopeptide A (CLA) from linen seeds, and its linear precursor on their biological activities and mechanisms of action, are reviewed. The modifications included truncation of the peptide chain, replacement of amino [...] Read more.

The consequences of manipulations in structure and amino acid composition of native cyclolinopeptide A (CLA) from linen seeds, and its linear precursor on their biological activities and mechanisms of action, are reviewed. The modifications included truncation of the peptide chain, replacement of amino acid residues with proteinogenic or non-proteinogenic ones, modifications of peptide bond, and others. The studies revealed changes in the immunosuppressive potency of these analogs investigated in a number of in vitro and in vivo experimental models, predominantly in rodents, as well as differences in their postulated mechanism of action. The modified peptides were compared with cyclosporine A and parent CLA. Some of the synthesized and investigated peptides show potential therapeutic usefulness. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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24 pages, 2831 KiB

Open AccessReview

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

by Andrea Caporale, Simone Adorinni, Doriano Lamba and Michele Saviano

Molecules 2021, 26(5), 1219; https://doi.org/10.3390/molecules26051219 - 25 Feb 2021

Cited by 17 | Viewed by 7148

Abstract

The self-recognition and self-assembly of biomolecules are spontaneous processes that occur in Nature and allow the formation of ordered structures, at the nanoscale or even at the macroscale, under thermodynamic and kinetic equilibrium as a consequence of specific and local interactions. In particular, [...] Read more.

The self-recognition and self-assembly of biomolecules are spontaneous processes that occur in Nature and allow the formation of ordered structures, at the nanoscale or even at the macroscale, under thermodynamic and kinetic equilibrium as a consequence of specific and local interactions. In particular, peptides and peptidomimetics play an elected role, as they may allow a rational approach to elucidate biological mechanisms to develop new drugs, biomaterials, catalysts, or semiconductors. The forces that rule self-recognition and self-assembly processes are weak interactions, such as hydrogen bonding, electrostatic attractions, and van der Waals forces, and they underlie the formation of the secondary structure (e.g., α-helix, β-sheet, polyproline II helix), which plays a key role in all biological processes. Here, we present recent and significant examples whereby design was successfully applied to attain the desired structural motifs toward function. These studies are important to understand the main interactions ruling the biological processes and the onset of many pathologies. The types of secondary structure adopted by peptides during self-assembly have a fundamental importance not only on the type of nano- or macro-structure formed but also on the properties of biomaterials, such as the types of interaction, encapsulation, non-covalent interaction, or covalent interaction, which are ultimately useful for applications in drug delivery. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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16 pages, 3982 KiB

Open AccessReview

From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBs): Perspectives of ARBs in COVID-19 Therapy

by John Matsoukas, Vasso Apostolopoulos, Anthony Zulli, Graham Moore, Konstantinos Kelaidonis, Kalliopi Moschovou and Thomas Mavromoustakos

Molecules 2021, 26(3), 618; https://doi.org/10.3390/molecules26030618 - 25 Jan 2021

Cited by 15 | Viewed by 7749

Abstract

The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the [...] Read more.

The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the active conformation. These studies on angiotensin II led to the discovery of Sarmesin, a type II angiotensin II antagonist, and the breakthrough non-peptide mimetic Losartan, the first in a series of sartans marketed as a new generation of anti-hypertensive drugs in the 1990s. Angiotensin II receptor blockers (ARBS) and angiotensin I converting enzyme inhibitors (ACEI) were recently reported to protect hypertensive patients infected with SARS-CoV-2. The renin–angiotensin system (RAS) inhibitors reduce excess angiotensin II and increase antagonist heptapeptides alamandine and aspamandine which counterbalance angiotensin II and maintain homeostasis and vasodilation. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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45 pages, 3038 KiB

Open AccessFeature PaperReview

A Global Review on Short Peptides: Frontiers and Perspectives

by Vasso Apostolopoulos, Joanna Bojarska, Tsun-Thai Chai, Sherif Elnagdy, Krzysztof Kaczmarek, John Matsoukas, Roger New, Keykavous Parang, Octavio Paredes Lopez, Hamideh Parhiz, Conrad O. Perera, Monica Pickholz, Milan Remko, Michele Saviano, Mariusz Skwarczynski, Yefeng Tang, Wojciech M. Wolf, Taku Yoshiya, Janusz Zabrocki, Piotr Zielenkiewicz, Maha AlKhazindar, Vanessa Barriga, Konstantinos Kelaidonis, Elham Mousavinezhad Sarasia and Istvan Toth Show full author list Hide full author list

Molecules 2021, 26(2), 430; https://doi.org/10.3390/molecules26020430 - 15 Jan 2021

Cited by 218 | Viewed by 21934

Abstract

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of [...] Read more.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide “drugs” initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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17 pages, 2309 KiB

Open AccessReview

Gemcitabine Peptide-Based Conjugates and Their Application in Targeted Tumor Therapy

by Aleksandra Hawryłkiewicz and Natalia Ptaszyńska

Molecules 2021, 26(2), 364; https://doi.org/10.3390/molecules26020364 - 12 Jan 2021

Cited by 15 | Viewed by 6445

Abstract

A major obstacle in tumor treatment is associated with the poor penetration of a therapeutic agent into the tumor tissue and with their adverse influence on healthy cells, which limits the dose of drug that can be safely administered to cancer patients. Gemcitabine [...] Read more.

A major obstacle in tumor treatment is associated with the poor penetration of a therapeutic agent into the tumor tissue and with their adverse influence on healthy cells, which limits the dose of drug that can be safely administered to cancer patients. Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first-line treatment for pancreatic cancer. The effect of gemcitabine is significantly weakened by its rapid plasma degradation. In addition, the systemic toxicity and drug resistance significantly reduce its chemotherapeutic efficacy. Up to now, many approaches have been made to improve the therapeutic index of gemcitabine. One of the recently developed approaches to improve conventional chemotherapy is based on the direct targeting of chemotherapeutics to cancer cells using the drug-peptide conjugates. In this work, we summarize recently published gemcitabine peptide-based conjugates and their efficacy in anticancer therapy. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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18 pages, 4439 KiB

Open AccessReview

Research Progress of the Biosynthesis of Natural Bio-Antibacterial Agent Pulcherriminic Acid in Bacillus

by Siqi Yuan, Xihao Yong, Ting Zhao, Yuan Li and Jun Liu

Molecules 2020, 25(23), 5611; https://doi.org/10.3390/molecules25235611 - 28 Nov 2020

Cited by 17 | Viewed by 4620

Abstract

Pulcherriminic acid is a cyclic dipeptide found mainly in Bacillus and yeast. Due to the ability of pulcherriminic acid to chelate Fe³⁺ to produce reddish brown pulcherrimin, microorganisms capable of synthesizing pulcherriminic acid compete with other microorganisms for environmental iron ions to [...] Read more.

Pulcherriminic acid is a cyclic dipeptide found mainly in Bacillus and yeast. Due to the ability of pulcherriminic acid to chelate Fe³⁺ to produce reddish brown pulcherrimin, microorganisms capable of synthesizing pulcherriminic acid compete with other microorganisms for environmental iron ions to achieve bacteriostatic effects. Therefore, studying the biosynthetic pathway and their enzymatic catalysis, gene regulation in the process of synthesis of pulcherriminic acid in Bacillus can facilitate the industrial production, and promote the wide application in food, agriculture and medicine industries. After initially discussing, this review summarizes current research on the synthesis of pulcherriminic acid by Bacillus, which includes the crystallization of key enzymes, molecular catalytic mechanisms, regulation of synthetic pathways, and methods to improve efficiency in synthesizing pulcherriminic acid and its precursors. Finally, possible applications of pulcherriminic acid in the fermented food, such as Chinese Baijiu, applying combinatorial biosynthesis will be summarized. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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12 pages, 2224 KiB

Open AccessReview

Review: Examining the Natural Role of Amphibian Antimicrobial Peptide Magainin

by Katelyn A. M. McMillan and Melanie R. Power Coombs

Molecules 2020, 25(22), 5436; https://doi.org/10.3390/molecules25225436 - 20 Nov 2020

Cited by 32 | Viewed by 4347

Abstract

Host defense peptides (HDPs) are a group of antimicrobial peptides (AMPs) that are crucial components of the innate immune system of many different organisms. These small peptides actively kill microbes and prevent infection. Despite the presence of AMPs in the amphibian immune system, [...] Read more.

Host defense peptides (HDPs) are a group of antimicrobial peptides (AMPs) that are crucial components of the innate immune system of many different organisms. These small peptides actively kill microbes and prevent infection. Despite the presence of AMPs in the amphibian immune system, populations of these organisms are in decline globally. Magainin is an AMP derived from the African clawed frog (Xenopus laevis) and has displayed potent antimicrobial effects against a wide variety of microbes. Included in this group of microbes are known pathogens of the African clawed frog and other amphibian species. Arguably, the most deleterious amphibious pathogen is Batrachochytrium dendrobatidis, a chytrid fungus. Investigating the mechanism of action of magainin can help understand how to effectively fight off infection. By understanding amphibian AMPs’ role in the frog, a potential conservation strategy can be developed for other species of amphibians that are susceptible to infections, such as the North American green frog (Rana clamitans). Considering that population declines of these organisms are occurring globally, this effort is crucial to protect not only these organisms but the ecosystems they inhabit as well. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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20 pages, 583 KiB

Open AccessReview

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

by Yamil Liscano, Jose Oñate-Garzón and Jean Paul Delgado

Molecules 2020, 25(18), 4245; https://doi.org/10.3390/molecules25184245 - 16 Sep 2020

Cited by 60 | Viewed by 6712

Abstract

Peptides are naturally produced by all organisms and exhibit a wide range of physiological, immunomodulatory, and wound healing functions. Furthermore, they can provide with protection against microorganisms and tumor cells. Their multifaceted performance, high selectivity, and reduced toxicity have positioned them as effective [...] Read more.

Peptides are naturally produced by all organisms and exhibit a wide range of physiological, immunomodulatory, and wound healing functions. Furthermore, they can provide with protection against microorganisms and tumor cells. Their multifaceted performance, high selectivity, and reduced toxicity have positioned them as effective therapeutic agents, representing a positive economic impact for pharmaceutical companies. Currently, efforts have been made to invest in the development of new peptides with antimicrobial and anticancer properties, but the poor stability of these molecules in physiological environments has triggered a bottleneck. Therefore, some tools, such as nanotechnology and in silico approaches can be applied as alternatives to try to overcome these obstacles. In silico studies provide a priori knowledge that can lead to the development of new anticancer peptides with enhanced biological activity and improved stability. This review focuses on the current status of research in peptides with dual antimicrobial–anticancer activity, including advances in computational biology using in silico analyses as a powerful tool for the study and rational design of these types of peptides. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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Other

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9 pages, 2104 KiB

Open AccessBrief Report

Binding Interactions of Peptide Aptamers

by Roger R. C. New, Tam T. T. Bui and Michal Bogus

Molecules 2020, 25(24), 6055; https://doi.org/10.3390/molecules25246055 - 21 Dec 2020

Cited by 7 | Viewed by 3220

Abstract

Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface [...] Read more.

Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding. Full article

(This article belongs to the Special Issue Advances in Research of Short Peptides)

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