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13 pages, 2300 KiB

Open AccessArticle

The Peptide Salamandrin-I Modulates Components Involved in Pyroptosis and Induces Cell Death in Human Leukemia Cell Line HL-60

by Amandda Évelin Silva-Carvalho, Nakaly Natiely de Oliveira, Julia Viana Lafetá Machado, Daniel Carneiro Moreira, Guilherme Dotto Brand, José Roberto S. A. Leite, Alexandra Plácido, Peter Eaton and Felipe Saldanha-Araujo

Pharmaceutics 2023, 15(7), 1864; https://doi.org/10.3390/pharmaceutics15071864 - 01 Jul 2023

Cited by 1 | Viewed by 963

Abstract

Amphibian secretions have been extensively investigated for the production of bioactive molecules. Salamandrin-I is an antioxidant peptide, isolated from the skin secretion of the fire salamander, that has induced no toxicity in microglia or erythrocytes. Importantly, the administration of antioxidants may constitute an [...] Read more.

Amphibian secretions have been extensively investigated for the production of bioactive molecules. Salamandrin-I is an antioxidant peptide, isolated from the skin secretion of the fire salamander, that has induced no toxicity in microglia or erythrocytes. Importantly, the administration of antioxidants may constitute an adequate therapeutic approach to cancer treatment. Here, with the purpose of better characterizing the therapeutic potential of salamandrin-I, we investigated whether this antioxidant peptide also exerts anticancer activity, using the human leukemia cell line HL-60 as a cancer model. Salamandrin-I treatment induced a significant reduction in HL-60 proliferation, which was accompanied by cell cycle arrest. Furthermore, the peptide-induced cell death showed a significant increase in the LDH release in HL-60 cells. The cellular toxicity exerted by salamandrin-I is possibly related to pyroptosis, since the HL-60 cells showed loss of mitochondrial membrane potential and hyperexpression of inflammasome components following the peptide treatment. This is the first demonstration of the anticancer potential of the salamandrin-I peptide. Such results are important, as they offer relevant insights into the field of cancer therapy and allow the design of future bioactive molecules using salamandrin-I as a template. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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16 pages, 5636 KiB

Open AccessArticle

Computational Modeling, High-Level Soluble Expression and In Vitro Cytotoxicity Assessment of Recombinant Pseudomonas aeruginosa Azurin: A Promising Anti-Cancer Therapeutic Candidate

by Shakira Aslam, Hafiz Muzzammel Rehman, Muhammad Zeeshan Sarwar, Ajaz Ahmad, Nadeem Ahmed, Muhammad Imran Amirzada, Hafiz Muhammad Rehman, Humaira Yasmin, Tariq Nadeem and Hamid Bashir

Pharmaceutics 2023, 15(7), 1825; https://doi.org/10.3390/pharmaceutics15071825 - 26 Jun 2023

Cited by 1 | Viewed by 1537

Abstract

Azurin is a natural protein produced by Pseudomonas aeruginosa that exhibits potential anti-tumor, anti-HIV, and anti-parasitic properties. The current study aimed to investigate the potential of azurin protein against breast cancer using both in silico and in vitro analyses. The amino acid sequence [...] Read more.

Azurin is a natural protein produced by Pseudomonas aeruginosa that exhibits potential anti-tumor, anti-HIV, and anti-parasitic properties. The current study aimed to investigate the potential of azurin protein against breast cancer using both in silico and in vitro analyses. The amino acid sequence of Azurin was used to predict its secondary and tertiary structures, along with its physicochemical properties, using online software. The resulting structure was validated and confirmed using Ramachandran plots and ERRAT2. The mature azurin protein comprises 128 amino acids, and the top-ranked structure obtained from I-TASSER was shown to have a molecular weight of 14 kDa and a quality factor of 100% by ERRAT2, with 87.4% of residues in the favored region of the Ramachandran plot. Docking and simulation studies of azurin protein were conducted using HDOCK and Desmond servers, respectively. The resulting analysis revealed that Azurin docked against p53 and EphB2 receptors demonstrated maximum binding affinity, indicating its potential to cause apoptosis. The recombinant azurin gene was successfully cloned and expressed in a BL21 (DE3) strain using a pET20b expression vector under the control of the pelB ladder, followed by IPTG induction. The azurin protein was purified to high levels using affinity chromatography, yielding 70 mg/L. In vitro cytotoxicity assay was performed using MCF-7 cells, revealing the significant cytotoxicity of the azurin protein to be 105 µg/mL. These findings highlight the potential of azurin protein as an anticancer drug candidate. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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17 pages, 2082 KiB

Open AccessArticle

DA7R: A 7-Letter Zip Code to Target PDAC

by Sofia Parrasia, Andrea Rossa, Nicola Roncaglia, Andrea Mattarei, Claudia Honisch, Ildikò Szabò, Paolo Ruzza and Lucia Biasutto

Pharmaceutics 2023, 15(5), 1508; https://doi.org/10.3390/pharmaceutics15051508 - 16 May 2023

Cited by 1 | Viewed by 1181

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and is among the most aggressive and still incurable cancers. Innovative and successful therapeutic strategies are extremely needed. Peptides represent a versatile and promising tool to achieve tumor targeting, thanks to [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and is among the most aggressive and still incurable cancers. Innovative and successful therapeutic strategies are extremely needed. Peptides represent a versatile and promising tool to achieve tumor targeting, thanks to their ability to recognize specific target proteins (over)expressed on the surface of cancer cells. A7R is one such peptide, binding neuropilin-1 (NRP-1) and VEGFR2. Since PDAC expresses these receptors, the aim of this study was to test if A7R-drug conjugates could represent a PDAC-targeting strategy. PAPTP, a promising mitochondria-targeted anticancer compound, was selected as the cargo for this proof-of-concept study. Derivatives were designed as prodrugs, using a bioreversible linker to connect PAPTP to the peptide. Both the retro-inverso (DA7R) and the head-to-tail cyclic (cA7R) protease-resistant analogs of A7R were tested, and a tetraethylene glycol chain was introduced to improve solubility. Uptake of a fluorescent DA7R conjugate, as well as of the PAPTP-DA7R derivative into PDAC cell lines was found to be related to the expression levels of NRP-1 and VEGFR2. Conjugation of DA7R to therapeutically active compounds or nanovehicles might allow PDAC-targeted drug delivery, improving the efficacy of the therapy and reducing off-target effects. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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14 pages, 2144 KiB

Open AccessArticle

Synthesis, Antiproliferative Effect and In Silico LogP Prediction of BIM-23052 Analogs Containing Tyr Instead of Phe

by Dancho Danalev, Ivan Iliev, Stefan Dobrev, Silvia Angelova, Stoiko Petrin, Tatyana Dzimbova, Elena Ivanova, Dessislava Borisova and Emilia Naydenova

Pharmaceutics 2023, 15(4), 1123; https://doi.org/10.3390/pharmaceutics15041123 - 31 Mar 2023

Cited by 2 | Viewed by 1058

Abstract

(1) Background: Hydrophobicity (or lipophilicity) is a limiting factor in the ability of molecules to pass through cell membranes and to perform their function. The ability to efficiently access cytosol is especially important when a synthetic compound has the potential to become a [...] Read more.

(1) Background: Hydrophobicity (or lipophilicity) is a limiting factor in the ability of molecules to pass through cell membranes and to perform their function. The ability to efficiently access cytosol is especially important when a synthetic compound has the potential to become a drug substance. D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂ (BIM-23052) is a linear analog of somatostatin with established in vitro GH-inhibitory activity in nanomolar (nm) concentrations and high affinity to different somatostatin receptors. (2) Methods: Series of analogs of BIM-23052 were synthesized where Phe residue(s) in the BIM-23052 molecule were replaced with Tyr using standard SPPS, Fmoc/t-Bu strategy. Analyses of target compounds were performed using HPLC/MS technique. Toxicity and antiproliferative activity were studied using in vitro NRU and MTT assays. The values of logP (partition coefficient in octanol/water) for BIM-23052 and its analogs were calculated. (3) Results: The obtained data show the best antiproliferative effect against studied cancer cells for compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr⁷-Thr-NH₂ (DD8), the most lipophilic compound according to the predicted logP values. (4) Conclusions: Multiple analyses of the obtained data reveal that compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr⁷-Thr-NH₂ (DD8) where one Phe is replaced by Tyr has the best combination of cytotoxicity, antiproliferative effect and hydrolytic stability. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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21 pages, 3834 KiB

Open AccessArticle

Therapeutic Effect of a Latent Form of Cortistatin in Experimental Inflammatory and Fibrotic Disorders

by Jenny Campos-Salinas, Margarita Barriga and Mario Delgado

Pharmaceutics 2022, 14(12), 2785; https://doi.org/10.3390/pharmaceutics14122785 - 13 Dec 2022

Viewed by 1364

Abstract

Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, [...] Read more.

Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, due to its promiscuity for several receptors expressed in various cells and tissues, represent two major drawbacks for the clinical translation of cortistatin-based therapies. Therefore, the design of new strategies focused on increasing the stability, bioavailability, and target specificity of cortistatin are lately demanded by the industry. Here, we generated by molecular engineering a new cortistatin-based prodrug formulation that includes, beside the bioactive cortistatin, a molecular-shield provided by the latency-associated protein of the transforming growth factor-β1 and a cleavage site specifically recognized by metalloproteinases, which are abundant in inflammatory/fibrotic foci. Using different models of sepsis, inflammatory bowel disease, scleroderma, and pulmonary fibrosis, we demonstrated that this latent form of cortistatin was a highly effective protection against these severe disorders. Noteworthy, from a therapeutic point of view, is that latent cortistatin seems to require significantly lower doses and fewer administrations than naive cortistatin to reach the same efficacy. Finally, the metalloproteinase-cleavage site was essential for the latent molecule to exert its therapeutic action. In summary, latent cortistatin emerges as a promising innovative therapeutic tool for treating chronic diseases of different etiologies with difficult clinical solutions and as a starting point for a rational development of prodrugs based on the use of bioactive peptides. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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23 pages, 3593 KiB

Open AccessArticle

Ramosin: The First Antibacterial Peptide Identified on Bolitoglossa ramosi Colombian Salamander

by Laura Medina, Fanny Guzmán, Claudio Álvarez, Jean Paul Delgado and Belfran Carbonell-M

Pharmaceutics 2022, 14(12), 2579; https://doi.org/10.3390/pharmaceutics14122579 - 23 Nov 2022

Cited by 3 | Viewed by 1364

Abstract

The discovery and improvements of antimicrobial peptides (AMPs) have become an alternative to conventional antibiotics. They are usually small and heat-stable peptides, exhibiting inhibitory activity against Gram-negative and Gram-positive bacteria. In this way, studies on broad-spectrum AMPs found in amphibians with the remarkable [...] Read more.

The discovery and improvements of antimicrobial peptides (AMPs) have become an alternative to conventional antibiotics. They are usually small and heat-stable peptides, exhibiting inhibitory activity against Gram-negative and Gram-positive bacteria. In this way, studies on broad-spectrum AMPs found in amphibians with the remarkable capability to regenerate a wide array of tissues are of particular interest in the search for new strategies to treat multidrug-resistant bacterial strains. In this work, the use of bioinformatic approaches such as sequence alignment with Fasta36 and prediction of antimicrobial activity allowed the identification of the Ramosin peptide from the de novo assembled transcriptome of the plethodontid salamander Bolitoglossa ramosi obtained from post-amputation of the upper limb tissue, heart, and intestine samples. BLAST analysis revealed that the Ramosin peptide sequence is unique in Bolitoglossa ramosi. The peptide was chemically synthesized, and physicochemical properties were characterized. Furthermore, the in vitro antimicrobial activity against relevant Gram-positive and Gram-negative human pathogenic bacteria was demonstrated. Finally, no effect against eukaryotic cells or human red blood cells was evidenced. This is the first antibacterial peptide identified from a Colombian endemic salamander with interesting antimicrobial properties and no hemolytic activity. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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18 pages, 4346 KiB

Open AccessArticle

Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides

by Vishnu Suresh Babu, Atish Kizhakeyil, Gagan Dudeja, Shyam S. Chaurasia, Veluchami Amutha Barathi, Stephane Heymans, Navin Kumar Verma, Rajamani Lakshminarayanan and Arkasubhra Ghosh

Pharmaceutics 2022, 14(11), 2507; https://doi.org/10.3390/pharmaceutics14112507 - 18 Nov 2022

Cited by 3 | Viewed by 1540

Abstract

Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities [...] Read more.

Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities against a broad range of pathogenic bacteria by dissipating the cytoplasmic membrane potential. Specifically, we identified two CAPs, named HC3 and HC5, that effectively killed a significant number of retinoblastoma (WERI-Rb1) cells (p ≤ 0.01). These two CAPs caused the shrinkage of WERI-Rb1 tumor spheroids (p ≤ 0.01), induced intrinsic apoptosis in WERI-Rb1 cells via activation of caspase 9 and caspase 3, cleaved the PARP protein, and triggered off the phosphorylation of p53 and γH2A.X. Combining HC3 or HC5 with the standard chemotherapeutic drug topotecan showed synergistic anti-cancer activities. Overall, these results suggest that HC3 and HC5 can be exploited as potential therapeutic agents in retinoblastoma as monotherapy or as adjunctive therapy to enhance the effectiveness of currently used treatment modalities. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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18 pages, 7546 KiB

Open AccessArticle

Antibacterial and Antifungal Properties of a Novel Antimicrobial Peptide GK-19 and Its Application in Skin and Soft Tissue Infections Induced by MRSA or Candida albicans

by Chenghua Song, Ruichao Wen, Jiaxuan Zhou, Xiaoyan Zeng, Zi Kou, Jia Zhang, Tao Wang, Pengkang Chang, Yi Lv and Rongqian Wu

Pharmaceutics 2022, 14(9), 1937; https://doi.org/10.3390/pharmaceutics14091937 - 13 Sep 2022

Cited by 6 | Viewed by 1697

Abstract

The increasing resistance of human pathogens promotes the development of novel antimicrobial agents. Due to the physical bactericidal mechanism of membrane disruption, antimicrobial peptides are considered as potential therapeutic candidates without inducing microbial resistance. Scorpion venom-derived peptide, Androctonus amoreuxi Antimicrobial Peptide 1 (AamAP1), [...] Read more.

The increasing resistance of human pathogens promotes the development of novel antimicrobial agents. Due to the physical bactericidal mechanism of membrane disruption, antimicrobial peptides are considered as potential therapeutic candidates without inducing microbial resistance. Scorpion venom-derived peptide, Androctonus amoreuxi Antimicrobial Peptide 1 (AamAP1), has been proved to have broad-spectrum antimicrobial properties. However, AamAP1 can induce hemolysis and shows strong toxicity against mammalian cells. Herein, the antimicrobial activity and mechanism of a novel synthetic antimicrobial peptide, GK-19, derived from AamAP1 and its derivatives, was evaluated. Five bacteria and three fungi were used to evaluate the antimicrobial effects of GK-19 in vitro. Scalded mice models combined with skin and soft tissue infections (SSTIs) were used to evaluate its applicability. The results indicated that GK-19 could not only inhibit Gram-positive and Gram-negative bacterial growth, but also kill fungi by disrupting the microbial cell membrane. Meanwhile, GK-19 showed negligible toxicity to mammalian cells, low hemolytic activity and high stability in plasma. Furthermore, in scalded mice models combined with SSTIs induced by either Methicillin-Resistant Staphylococcus aureus (MRSA) or Candida albicans, GK-19 showed significant antimicrobial and healing effects. Overall, it was demonstrated that GK-19 might be a promising drug candidate in the battle against drug-resistant bacterial and fungal infections. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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20 pages, 3449 KiB

Open AccessArticle

Bone-Targeted Delivery of Novokinin as an Alternative Treatment Option for Rheumatoid Arthritis

by Arina Ranjit, Sana Khajeh pour and Ali Aghazadeh-Habashi

Pharmaceutics 2022, 14(8), 1681; https://doi.org/10.3390/pharmaceutics14081681 - 12 Aug 2022

Cited by 2 | Viewed by 1529

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory bone destructive disorder that is orchestrated by multiple systems in the body, including Renin-Angiotensin System (RAS) and arachidonic acid (ArA) pathway. Current therapeutic options are not highly effective and are associated with severe side effects, including [...] Read more.

Rheumatoid arthritis (RA) is an autoimmune inflammatory bone destructive disorder that is orchestrated by multiple systems in the body, including Renin-Angiotensin System (RAS) and arachidonic acid (ArA) pathway. Current therapeutic options are not highly effective and are associated with severe side effects, including cardiovascular complications. Therefore, new safe and effective disease modulators are seriously needed. In this study, we investigate the anti-inflammatory effects of a synthetic peptide, novokinin, through Angiotensin Type (II) receptor (AT2R). Peptide drugs like novokinin suffer from plasma instability and short half-life. Thus, we developed a novel bone targeting novokinin conjugate (Novo Conj). It uses the bone as a reservoir for sustained release and protection from systemic degradation, improving stability and enhancing pharmacological efficacy. We tested Novo Conj’s anti-inflammatory effects in adjuvant-induced arthritis (AIA) rat model to prove our hypothesis by measuring various RAS and ArA pathway components. We observed that inflammation causes a significant imbalance in cardioprotective RAS components like ACE2, AT2R, and Ang 1-7 and increases the ArA inflammatory metabolites like hydroxyeicosatetraenoic acids (HETEs). Treatment with novokinin or Novo Conj restores balance in the RAS and favors the production of different epoxyeicosatrienoic acids (EETs), which are anti-inflammatory mediators. This study demonstrated that the bone-targeted delivery improved the stability and enhanced the anti-inflammatory effects of the parent peptide novokinin in AIA. These observations offer an efficacious alternative therapy for managing RA. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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Review

Jump to: Research

24 pages, 1494 KiB

Open AccessFeature PaperReview

Targeting Peptides: The New Generation of Targeted Drug Delivery Systems

by Biagio Todaro, Elisa Ottalagana, Stefano Luin and Melissa Santi

Pharmaceutics 2023, 15(6), 1648; https://doi.org/10.3390/pharmaceutics15061648 - 03 Jun 2023

Cited by 5 | Viewed by 2368

Abstract

Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production and stability in physiological environments; in recent years, they have been increasingly studied as targeting agents for several diseases, from tumors to central [...] Read more.

Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production and stability in physiological environments; in recent years, they have been increasingly studied as targeting agents for several diseases, from tumors to central nervous system disorders, also thanks to the ability of some of them to cross the blood–brain barrier. In this review, we will describe the techniques employed for their experimental and in silico design, as well as their possible applications. We will also discuss advancements in their formulation and chemical modifications that make them even more stable and effective. Finally, we will discuss how their use could effectively help to overcome various physiological problems and improve existing treatments. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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17 pages, 2597 KiB

Open AccessReview

Glycomimetic Peptides as Therapeutic Tools

by J. Kenneth Hoober and Laura L. Eggink

Pharmaceutics 2023, 15(2), 688; https://doi.org/10.3390/pharmaceutics15020688 - 17 Feb 2023

Viewed by 1802

Abstract

The entry of peptides into glycobiology has led to the development of a unique class of therapeutic tools. Although numerous and well-known peptides are active as endocrine regulatory factors that bind to specific receptors, and peptides have been used extensively as epitopes for [...] Read more.

The entry of peptides into glycobiology has led to the development of a unique class of therapeutic tools. Although numerous and well-known peptides are active as endocrine regulatory factors that bind to specific receptors, and peptides have been used extensively as epitopes for vaccine production, the use of peptides that mimic sugars as ligands of lectin-type receptors has opened a unique approach to modulate activity of immune cells. Ground-breaking work that initiated the use of peptides as tools for therapy identified sugar mimetics by screening phage display libraries. The peptides that have been discovered show significant potential as high-avidity, therapeutic tools when synthesized as multivalent structures. Advantages of peptides over sugars as drugs for immune modulation will be illustrated in this review. Full article

(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)

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