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Pharmaceutics
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Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial...
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Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 15273

Special Issue Editors

Dr. Toni Todorovski

E-Mail Website
Guest Editor
Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain
Interests: peptide synthesis; peptide–drug conjugates; BBB peptide shuttles; peptide medicinal chemistry; bioactive peptides; mass spectrometry
Prof. Dr. Daniela Kalafatovic

E-Mail Website
Guest Editor
Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
Interests: peptide nanomaterials; active peptides; catalytic peptides; peptide self-assembly; random peptide libraries
Prof. Dr. Michael A. Firer

E-Mail Website
Guest Editor
Department of Chemical Engineering and Adelson School of Medicine, Ariel University, Ariel 4070000, Israel
Interests: targeted drug delivery; peptide-drug-conjugates; Cellular immunotherapy; animal models of cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to the World Health Organization (WHO), antimicrobial resistance (AMR) is one of the top ten global public health threats that humanity is facing, while in 2019 cancer disease became the leading cause of death in the industrialized countries. Over the last two decades, peptide–drug conjugates (PDCs) have emerged as very important class of prodrugs to tackle various infectious diseases and cancers. PDC therapeutics combine one or more small drug molecules conjugated, most often, to a cell-penetrating peptide (CPP) either directly or through a biodegradable linker. This integration of two bioactive elements into a single entity often provides novel functionalities and improved bioavailability to treat conditions where conventional drugs are ineffective.

With this Special Issue we would like to provide readers with the latest developments and innovations in the design and synthesis of peptide–drug conjugates that are used to target various infectious diseases and cancers. Therefore, we are interested in articles related to new chemical and conjugation strategies for developing efficient antimicrobial and anticancer PDCs using in vitro models, in vivo trials and with possible application in the pharmaceutical industry. 

Dr. Toni Todorovski
Prof. Dr. Daniela Kalafatovic
Prof. Dr. Michael A. Firer
Guest Editors

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Keywords

  • peptide–drug conjugates
  • chemical biology
  • antimicrobial therapy
  • anticancer therapy
  • antivirals
  • peptide therapeutics

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Published Papers (5 papers)

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Research

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25 pages, 6785 KiB  
Article
Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates
by George Leonidis, Anastasia Koukiali, Ioanna Sigala, Katerina Tsimaratou, Dimitris Beis, Thomas Giannakouros, Eleni Nikolakaki and Vasiliki Sarli
Pharmaceutics 2023, 15(2), 381; https://doi.org/10.3390/pharmaceutics15020381 - 22 Jan 2023
Cited by 1 | Viewed by 2898
Abstract
Peptide–drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was [...] Read more.
Peptide–drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the ανβ3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases. Full article
(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)
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19 pages, 2258 KiB  
Article
Conjugation of a Cationic Cell-Penetrating Peptide with a Novel Kunitzin-like Trypsin Inhibitor: New Insights for Enhancement of Peptide Bioactivities
by Junting Yao, Weining Yin, Yuqing Chen, Xiaoling Chen, Yangyang Jiang, Tao Wang, Chengbang Ma, Mei Zhou, Tianbao Chen, Chris Shaw and Lei Wang
Pharmaceutics 2022, 14(9), 1805; https://doi.org/10.3390/pharmaceutics14091805 - 27 Aug 2022
Cited by 4 | Viewed by 2340
Abstract
Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent [...] Read more.
Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent serine protease inhibitory activity. However, poor transmembrane permeability of these molecules has largely hindered the study of the full spectrum of their biological actions. As a result, this study aimed to extend the biological activities of amphibian KTIs by their conjugation to cationic CPPs. Herein, a novel peptide (kunitzin-OV2) and its phenylalanine-substituted analogue F9-kunitzin-OV2 (F9-KOV2) were evaluated for inhibition of trypsin/chymotrypsin and showed weak antibacterial activity against Escherichia coli (E. coli). As expected, the conjugation to TAT peptide did not increase membrane lysis compared with the original kunitzin-OV2, but effectively assisted this complex to enter cells. TAT-kunitzin-OV2 (TAT-KOV2) exhibited a 32-fold increase in antibacterial activity and an enhanced bactericidal rate against E. coli. In addition, the conjugation enabled the parent peptides to exhibit antiproliferative activity against cancer cells. Interestingly, TAT-F9-kunitzin-OV2 (TAT-F9-KOV2) showed stronger antiproliferative activity against human breast cancer (MCF-7) and human glioblastoma (U251MG) cell lines, which TAT-KOV2 did not possess. Moreover, TAT-F9-KOV2 showed a 20–25-fold increase in antiproliferative capacity against human lung cancer (H157, H460) cell lines compared with TAT-KOV2. Therefore, the conjugation of CPPs effectively solves the problem of cell penetration that short KTIs lack and provides evidence for new potential applications for their subsequent development as new antibacterial and anticancer agents. Full article
(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)
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18 pages, 6389 KiB  
Article
Novel Cyclic Peptides for Targeting EGFR and EGRvIII Mutation for Drug Delivery
by Olga Furman, Alisa Zaporozhets, Dror Tobi, Andrii Bazylevich, Michael A. Firer, Leonid Patsenker, Gary Gellerman and Bat Chen R. Lubin
Pharmaceutics 2022, 14(7), 1505; https://doi.org/10.3390/pharmaceutics14071505 - 20 Jul 2022
Cited by 17 | Viewed by 3052
Abstract
The epidermal growth factor–epidermal growth factor receptor (EGF-EGFR) pathway has become the main focus of selective chemotherapeutic intervention. As a result, two classes of EGFR inhibitors have been clinically approved, namely monoclonal antibodies and small molecule kinase inhibitors. Despite an initial good response [...] Read more.
The epidermal growth factor–epidermal growth factor receptor (EGF-EGFR) pathway has become the main focus of selective chemotherapeutic intervention. As a result, two classes of EGFR inhibitors have been clinically approved, namely monoclonal antibodies and small molecule kinase inhibitors. Despite an initial good response rate to these drugs, most patients develop drug resistance. Therefore, new treatment approaches are needed. In this work, we aimed to find a new EGFR-specific, short cyclic peptide, which could be used for targeted drug delivery. Phage display peptide technology and biopanning were applied to three EGFR expressing cells, including cells expressing the EGFRvIII mutation. DNA from the internalized phage was extracted and the peptide inserts were sequenced using next-generation sequencing (NGS). Eleven peptides were selected for further investigation using binding, internalization, and competition assays, and the results were confirmed by confocal microscopy and peptide docking. Among these eleven peptides, seven showed specific and selective binding and internalization into EGFR positive (EGFR+ve) cells, with two of them—P6 and P9—also demonstrating high specificity for non-small cell lung cancer (NSCLC) and glioblastoma cells, respectively. These peptides were chemically conjugated to camptothecin (CPT). The conjugates were more cytotoxic to EGFR+ve cells than free CPT. Our results describe a novel cyclic peptide, which can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation. Full article
(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)
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Review

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20 pages, 2306 KiB  
Review
Multimeric RGD-Based Strategies for Selective Drug Delivery to Tumor Tissues
by Jordan Cossu, Fabien Thoreau and Didier Boturyn
Pharmaceutics 2023, 15(2), 525; https://doi.org/10.3390/pharmaceutics15020525 - 4 Feb 2023
Cited by 14 | Viewed by 3611
Abstract
RGD peptides have received a lot of attention over the two last decades, in particular to improve tumor therapy through the targeting of the αVβ3 integrin receptor. This review focuses on the molecular design of multimeric RGD compounds, as well as the design [...] Read more.
RGD peptides have received a lot of attention over the two last decades, in particular to improve tumor therapy through the targeting of the αVβ3 integrin receptor. This review focuses on the molecular design of multimeric RGD compounds, as well as the design of suitable linkers for drug delivery. Many examples of RGD–drug conjugates have been developed, and we show the importance of RGD constructs to enhance binding affinity to tumor cells, as well as their drug uptake. Further, we also highlight the use of RGD peptides as theranostic systems, promising tools offering dual modality, such as tumor diagnosis and therapy. In conclusion, we address the challenging issues, as well as ongoing and future development, in comparison with large molecules, such as monoclonal antibodies. Full article
(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)
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17 pages, 1331 KiB  
Review
Antiviral Peptide-Based Conjugates: State of the Art and Future Perspectives
by Toni Todorovski, Daniela Kalafatovic and David Andreu
Pharmaceutics 2023, 15(2), 357; https://doi.org/10.3390/pharmaceutics15020357 - 20 Jan 2023
Cited by 5 | Viewed by 2497
Abstract
Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim millions of deaths per year worldwide and have become a serious challenge to global human health in our century. Viral infections are particularly notable in this regard, not only because humankind is [...] Read more.
Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim millions of deaths per year worldwide and have become a serious challenge to global human health in our century. Viral infections are particularly notable in this regard, not only because humankind is facing some of the deadliest viral pandemics in recent history, but also because the arsenal of drugs to combat the high levels of mutation, and hence the antigenic variability of (mostly RNA) viruses, is disturbingly scarce. Therefore, the search for new antivirals able to successfully fight infection with minimal or no adverse effects on the host is a pressing task. Traditionally, antiviral therapies have relied on relatively small-sized drugs acting as proteases, polymerases, integrase inhibitors, etc. In recent decades, novel approaches involving targeted delivery such as that achieved by peptide–drug conjugates (PDCs) have gained attention as alternative (pro)drugs for tackling viral diseases. Antiviral PDC therapeutics typically involve one or more small drug molecules conjugated to a cell-penetrating peptide (CPP) carrier either directly or through a linker. Such integration of two bioactive elements into a single molecular entity is primarily aimed at achieving improved bioavailability in conditions where conventional drugs are challenged, but may also turn up novel unexpected functionalities and applications. Advances in peptide medicinal chemistry have eased the way to antiviral PDCs, but challenges remain on the way to therapeutic success. In this paper, we review current antiviral CPP–drug conjugates (antiviral PDCs), with emphasis on the types of CPP and antiviral cargo. We integrate the conjugate and the chemical approaches most often applied to combine both entities. Additionally, we comment on various obstacles faced in the design of antiviral PDCs and on the future outlooks for this class of antiviral therapeutics. Full article
(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)
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