Chemically Enhanced Peptide and Protein Therapeutics

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 53748

Special Issue Editors


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Guest Editor
GEMAT, Department of Bioengineering, Institut Químic de Sarrià, Universitat Ramon Llull, 08017 Barcelona, Spain
Interests: the generation of new chemically enhanced peptide and protein therapeutics

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Guest Editor
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
Interests: oral delivery; nose-to-brain delivery; peptide/protein delivery

Special Issue Information

Dear Colleagues,

The approval of peptide and protein therapeutics by medicinal regulatory agencies is on the rise. Biotherapeutics have exquisite selectivity and have proven capable of engaging targets considered undruggable with small molecules. However, natural peptides and proteins may present limited circulation half-lives or limited cell-killing efficiency. Chemistry provides many opportunities to address these and other challenges, thereby increasing the efficacy of biotherapeutics. Some examples of “chemical enhancement” include peptide cyclization to increase protease stability, the insertion of noncanonical amino acids with functional groups that increase target affinity, anchoring polymer chains to reduce glomerular filtration, and the conjugation of cytotoxic molecules to enhance therapeutic efficacy. In this Special Issue, we welcome research articles reporting recent advances in this rapidly growing field, including chemically modified peptides and proteins as stand-alone therapeutics or targeting moieties.

Dr. Benjamí Oller-Salvia
Dr. Noriyasu Kamei
Guest Editors

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Keywords

  • noncanonical amino acids
  • peptide therapeutics
  • targeting peptides
  • peptidomimetics
  • protein therapeutics
  • antibody–drug conjugates

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

4 pages, 214 KiB  
Editorial
Chemically Enhanced Peptide and Protein Therapeutics
by Cristina Díaz-Perlas and Benjamí Oller-Salvia
Pharmaceutics 2023, 15(3), 827; https://doi.org/10.3390/pharmaceutics15030827 - 3 Mar 2023
Viewed by 1220
Abstract
Proteins and peptides are on the rise as therapeutic agents and represent a higher percentage of approved drugs each year: 24% in 2021 vs [...] Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)

Research

Jump to: Editorial, Review

18 pages, 3742 KiB  
Article
Linker-Free Synthesis of Antimicrobial Peptides Using a Novel Cleavage Reagent: Characterisation of the Molecular and Ionic Composition by nanoESI-HR MS
by Roser Segovia, Mireia Díaz-Lobo, Yolanda Cajal, Marta Vilaseca and Francesc Rabanal
Pharmaceutics 2023, 15(4), 1310; https://doi.org/10.3390/pharmaceutics15041310 - 21 Apr 2023
Cited by 1 | Viewed by 2415
Abstract
The efficient preparation of novel bioactive peptide drugs requires the availability of reliable and accessible chemical methodologies together with suitable analytical techniques for the full characterisation of the synthesised compounds. Herein, we describe a novel acidolytic method with application to the synthesis of [...] Read more.
The efficient preparation of novel bioactive peptide drugs requires the availability of reliable and accessible chemical methodologies together with suitable analytical techniques for the full characterisation of the synthesised compounds. Herein, we describe a novel acidolytic method with application to the synthesis of cyclic and linear peptides involving benzyl-type protection. The process consists of the in situ generation of anhydrous hydrogen bromide and a trialkylsilyl bromide that acts as protic and Lewis acid reagents. This method proved to be useful to effectively remove benzyl-type protecting groups and cleave Fmoc/tBu assembled peptides directly attached to 4-methylbenzhydrylamine (MBHA) resins with no need for using mild trifluoroacetic acid labile linkers. The novel methodology was successful in synthesising three antimicrobial peptides, including the cyclic compound polymyxin B3, dusquetide, and RR4 heptapeptide. Furthermore, electrospray mass spectrometry (ESI-MS) is successfully used for the full characterisation of both the molecular and ionic composition of the synthetic peptides. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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15 pages, 1892 KiB  
Article
Liposomal Formulations of a Polyleucine–Antigen Conjugate as Therapeutic Vaccines against Cervical Cancer
by Farrhana Z. Firdaus, Stacey Bartlett, Waleed M. Hussein, Lantian Lu, Quentin Wright, Wenbin Huang, Ummey J. Nahar, Jieru Yang, Mattaka Khongkow, Margaret Veitch, Prashamsa Koirala, Uracha R. Ruktanonchai, Michael J. Monteiro, Jazmina L. Gonzalez Cruz, Rachel J. Stephenson, James W. Wells, Istvan Toth and Mariusz Skwarczynski
Pharmaceutics 2023, 15(2), 602; https://doi.org/10.3390/pharmaceutics15020602 - 10 Feb 2023
Cited by 5 | Viewed by 2451
Abstract
Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and [...] Read more.
Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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12 pages, 3128 KiB  
Article
Binding and Kinetic Analysis of Human Protein Phosphatase PP2A Interactions with Caspase 9 Protein and the Interfering Peptide C9h
by Karim Dorgham, Samuel Murail, Pierre Tuffery, Eric Savier, Jeronimo Bravo and Angelita Rebollo
Pharmaceutics 2022, 14(10), 2055; https://doi.org/10.3390/pharmaceutics14102055 - 27 Sep 2022
Cited by 2 | Viewed by 1594
Abstract
The serine/threonine phosphatase PP2A and the cysteine protease Caspase 9 are two proteins involved in physiological and pathological processes, including cancer and apoptosis. We previously demonstrated the interaction between Caspase 9 and PP2A and identified the C9h peptide, corresponding to the binding site [...] Read more.
The serine/threonine phosphatase PP2A and the cysteine protease Caspase 9 are two proteins involved in physiological and pathological processes, including cancer and apoptosis. We previously demonstrated the interaction between Caspase 9 and PP2A and identified the C9h peptide, corresponding to the binding site of Caspase 9 to PP2A. This interfering peptide can modulate Caspase 9/PP2A interaction leading to a strong therapeutic effect in vitro and in vivo in mouse models of tumor progression. In this manuscript, we investigate (I) the peptide binding to PP2A combining docking with molecular dynamics and (II) the secondary structure of the peptide using CD spectroscopy. Additionally, we compare the binding affinity, using biolayer interferometry, of the wild-type protein PP2A with Caspase 9 and vice versa to that observed between the PP2A protein and the interfering peptide C9h. This result strongly encourages the use of peptides as new therapeutics against cancer, as shown for the C9h peptide already in clinical trial. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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15 pages, 2684 KiB  
Article
Colistin Interaction and Surface Changes Associated with mcr-1 Conferred Plasmid Mediated Resistance in E. coli and A. veronii Strains
by Firdoos Ahmad Gogry, Mohammad Tahir Siddiqui, Insha Sultan, Fohad Mabood Husain, Abdulaziz A. Al-Kheraif, Asghar Ali and Qazi Mohd. Rizwanul Haq
Pharmaceutics 2022, 14(2), 295; https://doi.org/10.3390/pharmaceutics14020295 - 27 Jan 2022
Cited by 17 | Viewed by 3986
Abstract
Colistin, a polycationic antimicrobial peptide, is one of the last-resort antibiotics for treating infections caused by carbapenem-resistant Gram-negative bacteria. The antibacterial activity of colistin occurs through electrostatic interaction between the polycationic peptide group of colistin and the negatively charged phosphate groups of lipid [...] Read more.
Colistin, a polycationic antimicrobial peptide, is one of the last-resort antibiotics for treating infections caused by carbapenem-resistant Gram-negative bacteria. The antibacterial activity of colistin occurs through electrostatic interaction between the polycationic peptide group of colistin and the negatively charged phosphate groups of lipid A membrane. This study investigated the interaction of colistin with the outer membrane and surface constituents of resistant and susceptible strains of Escherichia coli and Aeromonas veronii harboring mcr-1 resistance gene. Bacterial membrane and lipopolysaccharide used in this study were isolated from susceptible as well as colistin-resistant strains of E. coli and A. veronii. Interaction of colistin with the bacterial surface was studied by deoxycholate and lysozyme sensitivity test, N-phenyl-1-naphthylamine (NPN) uptake assay, Atomic force microscopy (AFM), Zeta potential measurements and 1H NMR. The binding affinity of colistin was found to be lower with outer membrane from resistant strains in comparison with the susceptible strains. Colistin exposure enhances the outer membrane permeability of the susceptible strains to deoxycholate and lysozyme. However, on the other hand, colistin dose of 256 µg/mL did not permeabilize the outer membrane of resistant bacteria. The NPN permeability in resistant strains was greater in comparison with susceptible strains. Atomic force microscopy images depicted smooth, featherless and deformed membranes in treated susceptible cells. Contrary to the above, resistant treated cells displayed surface roughness topography even at 256 µg/mL colistin concentration. Surface charge alterations were confirmed by Zeta potential measurements as a function of the growth phase. Mid-logarithmic phase susceptible strains showed a greater negative charge than resistant strains upon exposure to colistin. However, there was no statistical variation in the Zeta potential measurements between resistant and susceptible strains at the stationary phase. NMR analysis revealed line broadening in susceptible strains with increasing colistin: LPS aggregates mass ratio. Moreover, resistant strains did not show line broadening for the outer membrane, even at the highest mass ratio. The findings of this study suggest that the resistant strains of E. coli and A. veronii can block the electrostatic contact between the cationic peptide and anionic lipid A component that drives the first phase of colistin action, thereby preventing hydrophobically driven second-tier action of colistin on the outer lipopolysaccharide layer. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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14 pages, 3539 KiB  
Article
Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
by Naroa Serna, Aïda Falgàs, Annabel García-León, Ugutz Unzueta, Yáiza Núñez, Alejandro Sánchez-Chardi, Carlos Martínez-Torró, Ramón Mangues, Esther Vazquez, Isolda Casanova and Antonio Villaverde
Pharmaceutics 2022, 14(1), 192; https://doi.org/10.3390/pharmaceutics14010192 - 14 Jan 2022
Cited by 8 | Viewed by 2185
Abstract
The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots [...] Read more.
The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4+ lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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17 pages, 3702 KiB  
Article
Unveiling the Membrane and Cell Wall Action of Antimicrobial Cyclic Lipopeptides: Modulation of the Spectrum of Activity
by Roser Segovia, Judith Solé, Ana Maria Marqués, Yolanda Cajal and Francesc Rabanal
Pharmaceutics 2021, 13(12), 2180; https://doi.org/10.3390/pharmaceutics13122180 - 17 Dec 2021
Cited by 11 | Viewed by 3083
Abstract
Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently [...] Read more.
Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently needed. Colistin and polymyxin B are natural antibiotics considered as last resort drugs for multi-resistant infections, but their use is limited because of neuro- and nephrotoxicity. We previously reported a series of synthetic analogues inspired in natural polymyxins with a flexible scaffold that allows multiple modifications to improve activity and reduce toxicity. In this work, we focus on modifications in the hydrophobic domains, describing analogues that broaden or narrow the spectrum of activity including both Gram-positive and Gram-negative bacteria, with MICs in the low µM range and low hemolytic activity. Using biophysical methods, we explore the interaction of the new molecules with model membranes that mimic the bacterial inner and outer membranes, finding a selective effect on anionic membranes and a mechanism of action based on the alteration of membrane function. Transmission electron microscopy observation confirms that polymyxin analogues kill microbial cells primarily by damaging membrane integrity. Redistribution of the hydrophobicity within the polymyxin molecule seems a plausible approach for the design and development of safer and more selective antibiotics. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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15 pages, 2738 KiB  
Article
Enhanced Cellular Uptake of H-Chain Human Ferritin Containing Gold Nanoparticles
by Italo Moglia, Margarita Santiago, Simon Guerrero, Mónica Soler, Alvaro Olivera-Nappa and Marcelo J. Kogan
Pharmaceutics 2021, 13(11), 1966; https://doi.org/10.3390/pharmaceutics13111966 - 19 Nov 2021
Cited by 3 | Viewed by 2321
Abstract
Gold nanoparticles (AuNP) capped with biocompatible layers have functional optical, chemical, and biological properties as theranostic agents in biomedicine. The ferritin protein containing in situ synthesized AuNPs has been successfully used as an effective and completely biocompatible nanocarrier for AuNPs in human cell [...] Read more.
Gold nanoparticles (AuNP) capped with biocompatible layers have functional optical, chemical, and biological properties as theranostic agents in biomedicine. The ferritin protein containing in situ synthesized AuNPs has been successfully used as an effective and completely biocompatible nanocarrier for AuNPs in human cell lines and animal experiments in vivo. Ferritin can be uptaken by different cell types through receptor-mediated endocytosis. Despite these advantages, few efforts have been made to evaluate the toxicity and cellular internalization of AuNP-containing ferritin nanocages. In this work, we study the potential of human heavy-chain (H) and light-chain (L) ferritin homopolymers as nanoreactors to synthesize AuNPs and their cytotoxicity and cellular uptake in different cell lines. The results show very low toxicity of ferritin-encapsulated AuNPs on different human cell lines and demonstrate that efficient cellular ferritin uptake depends on the specific H or L protein chains forming the ferritin protein cage and the presence or absence of metallic cargo. Cargo-devoid apoferritin is poorly internalized in all cell lines, and the highest ferritin uptake was achieved with AuNP-loaded H-ferritin homopolymers in transferrin-receptor-rich cell lines, showing more than seven times more uptake than apoferritin. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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15 pages, 3371 KiB  
Article
Disclosure of a Promising Lead to Tackle Complicated Skin and Skin Structure Infections: Antimicrobial and Antibiofilm Actions of Peptide PP4-3.1
by Ana Gomes, Lucinda J. Bessa, Iva Fernandes, Ricardo Ferraz, Cláudia Monteiro, M. Cristina L. Martins, Nuno Mateus, Paula Gameiro, Cátia Teixeira and Paula Gomes
Pharmaceutics 2021, 13(11), 1962; https://doi.org/10.3390/pharmaceutics13111962 - 19 Nov 2021
Cited by 8 | Viewed by 2454
Abstract
Efficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the [...] Read more.
Efficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the new hope for the post-antibiotic era. Thus, future management of cSSTI may include use of peptides that, on the one hand, behave as AMP and, on the other, are able to promote fast and correct skin rebuilding. As such, we combined the well-known cosmeceutical pentapeptide-4 (PP4), devoid of antimicrobial action but possessing collagenesis-boosting properties, with the AMP 3.1, to afford the chimeric peptide PP4-3.1. We further produced its N-methyl imidazole derivative, MeIm-PP4-3.1. Both peptide-based constructs were evaluated in vitro against Gram-negative bacteria, Gram-positive bacteria, and Candida spp. fungi. Additionally, the antibiofilm activity, the toxicity to human keratinocytes, and the activity against S. aureus in simulated wound fluid (SWF) were assessed. The chimeric peptide PP4-3.1 stood out for its potent activity against Gram-positive and Gram-negative bacteria, including against MDR clinical isolates (0.8 ≤ MIC ≤ 5.7 µM), both in planktonic form and in biofilm matrix. The peptide was also active against three clinically relevant species of Candida fungi, with an overall performance superior to that of fluconazole. Altogether, data reveal that PP4-3.1 is as a promising lead for the future development of new topical treatments for severe skin infections. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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18 pages, 3779 KiB  
Article
Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy
by Fadia Zaknoon, Ohad Meir and Amram Mor
Pharmaceutics 2021, 13(11), 1947; https://doi.org/10.3390/pharmaceutics13111947 - 17 Nov 2021
Cited by 5 | Viewed by 2118
Abstract
We describe the design and attributes of a linear pentapeptide-like derivative (C14(ω5)OOc10O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to [...] Read more.
We describe the design and attributes of a linear pentapeptide-like derivative (C14(ω5)OOc10O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to sensitize resilient GNB to hydrophobic and/or efflux-substrate antibiotics, whereas in their absence, C14(ω5)OOc10O only briefly delayed bacterial proliferation. Instead, at low micromolar concentrations, the lipopeptide has rapidly lowered bacterial proton and ATP levels, although significantly less than upon treatment with its bactericidal analog. Mechanistic studies support a two-step scenario providing a plausible explanation for the lipopeptide’s biological outcomes against GNB: initially, C14(ω5)OOc10O permeabilizes the outer membrane similarly to polymyxin B, albeit in a manner not necessitating as much LPS-binding affinity. Subsequently, C14(ω5)OOc10O would interact with the inner membrane gently yet intensively enough to restrain membrane-protein functions such as drug efflux and/or ATP generation, while averting the harsher inner membrane perturbations that mediate the fatal outcome associated with bactericidal peers. Preliminary in vivo studies where skin wound infections were introduced in mice, revealed a significant efficacy in affecting bacterial viability upon topical treatment with creams containing C14(ω5)OOc10O, whereas synergistic combination therapies were able to secure the pathogen’s eradication. Further, capitalizing on the finding that C14(ω5)OOc10O plasma-potentiating concentrations were attainable in mice blood at sub-maximal tolerated doses, we used a urinary tract infection model to acquire evidence for the lipopeptide’s systemic capacity to reduce the kidney’s bacterial loads. Collectively, the data establish the role of C14(ω5)OOc10O as a compelling antibacterial potentiator and suggest its drug-like potential. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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18 pages, 2768 KiB  
Article
Novel Nanocombinations of l-Tryptophan and l-Cysteine:  Preparation, Characterization, and Their Applications for Antimicrobial and Anticancer Activities
by Ahmed I. Abd-Elhamid, Hamada El-Gendi, Abdallah E. Abdallah and Esmail M. El-Fakharany
Pharmaceutics 2021, 13(10), 1595; https://doi.org/10.3390/pharmaceutics13101595 - 1 Oct 2021
Cited by 12 | Viewed by 1781
Abstract
Tungsten oxide WO3 nanoparticles (NPs) were prepared in a form of nanosheets with homogeneous size and dimensions in one step through acid precipitation using a cation exchange column. The resulting WO3 nanosheet surface was decorated with one of the two amino [...] Read more.
Tungsten oxide WO3 nanoparticles (NPs) were prepared in a form of nanosheets with homogeneous size and dimensions in one step through acid precipitation using a cation exchange column. The resulting WO3 nanosheet surface was decorated with one of the two amino acids (AAs) l-tryptophan (Trp) or l-cysteine (Cys) and evaluated for their dye removal, antimicrobial, and antitumor activities. A noticeable improvement in the biological activity of WO3 NPs was detected upon amino acid modification compared to the original WO3. The prepared WO3-Trp and WO3-Cys exhibited strong dye removal activity toward methylene blue and safranin dyes with complete dye removal (100%) after 6 h. WO3-Cys and WO3-Trp NPs revealed higher broad-spectrum antibacterial activity toward both Gram-negative and Gram-positive bacteria, with strong antifungal activity toward Candida albicans. Anticancer results of the modified WO3-Cys and WO3-Trp NPs against various kinds of cancer cells, including MCF-7, Caco-2, and HepG-2 cells, indicate that they have a potent effect in a dose-dependent manner with high selectivity to cancer cells and safety against normal cells. The expression levels of E2F2 and Bcl-2 genes were found to be suppressed after treatment with both WO3-Cys and WO3-Trp NPs more than 5-FU-treated cells. While expression level of the p53 gene in all tested cells was up-regulated after treatment 5–8 folds more as compared to untreated cells. The docking results confirmed the ability of both NPs to bind to the p53 gene with relevant potency in binding to other tested gens and participation of cysteine SH-functional group in such interaction. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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Review

Jump to: Editorial, Research

54 pages, 3644 KiB  
Review
A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future
by Emily Holz, Martine Darwish, Devin B. Tesar and Whitney Shatz-Binder
Pharmaceutics 2023, 15(2), 600; https://doi.org/10.3390/pharmaceutics15020600 - 10 Feb 2023
Cited by 16 | Viewed by 7849
Abstract
Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. [...] Read more.
Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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27 pages, 9971 KiB  
Review
Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate
by Rotimi Sheyi, Beatriz G. de la Torre and Fernando Albericio
Pharmaceutics 2022, 14(2), 396; https://doi.org/10.3390/pharmaceutics14020396 - 11 Feb 2022
Cited by 49 | Viewed by 11848
Abstract
As one of the major therapeutic options for cancer treatment, chemotherapy has limited selectivity against cancer cells. Consequently, this therapeutic strategy offers a small therapeutic window with potentially high toxicity and thus limited efficacy of doses that can be tolerated by patients. Antibody-drug [...] Read more.
As one of the major therapeutic options for cancer treatment, chemotherapy has limited selectivity against cancer cells. Consequently, this therapeutic strategy offers a small therapeutic window with potentially high toxicity and thus limited efficacy of doses that can be tolerated by patients. Antibody-drug conjugates (ADCs) are an emerging class of anti-cancer therapeutic drugs that can deliver highly cytotoxic molecules directly to cancer cells. To date, twelve ADCs have received market approval, with several others in clinical stages. ADCs have become a powerful class of therapeutic agents in oncology and hematology. ADCs consist of recombinant monoclonal antibodies that are covalently bound to cytotoxic chemicals via synthetic linkers. The linker has a key role in ADC outcomes because its characteristics substantially impact the therapeutic index efficacy and pharmacokinetics of these drugs. Stable linkers and ADCs can maintain antibody concentration in blood circulation, and they do not release the cytotoxic drug before it reaches its target, thus resulting in minimum off-target effects. The linkers used in ADC development can be classified as cleavable and non-cleavable. The former, in turn, can be grouped into three types: hydrazone, disulfide, or peptide linkers. In this review, we highlight the various linkers used in ADC development and their design strategy, release mechanisms, and future perspectives. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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17 pages, 1797 KiB  
Review
Disrupting GPCR Complexes with Smart Drug-like Peptides
by Maria Gallo, Sira Defaus and David Andreu
Pharmaceutics 2022, 14(1), 161; https://doi.org/10.3390/pharmaceutics14010161 - 11 Jan 2022
Cited by 10 | Viewed by 2903
Abstract
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure [...] Read more.
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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16 pages, 3314 KiB  
Review
Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics
by Maria C. Lucana, Yolanda Arruga, Emilia Petrachi, Albert Roig, Roberta Lucchi and Benjamí Oller-Salvia
Pharmaceutics 2021, 13(12), 2065; https://doi.org/10.3390/pharmaceutics13122065 - 2 Dec 2021
Cited by 22 | Viewed by 3651
Abstract
Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance [...] Read more.
Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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