Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

Serna, Naroa; Carratalá, Jose Vicente; Conchillo-Solé, Òscar; Martínez-Torró, Carlos; Unzueta, Ugutz; Mangues, Ramón; Ferrer-Miralles, Neus; Daura, Xavier; Vázquez, Esther; Villaverde, Antonio

doi:10.3390/pharmaceutics13111922

Cited by 7 publications

(8 citation statements)

References 121 publications

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“…The modular protein T22-GFP-H6 has been used in this study as a model. T22 (red box) is a cationic peptide targeting CXCR4 [53], L (brown box) is a peptidic linker (GGRSSRSS) that provides flexibility, GFP (green box) is an enhanced GFP and H6 is a hexahistidine tag (black box) [54,55]. H6 is useful for both chromatographic purification of the protein [54][55][56][57] and cation-mediated assembly [55,58].…”

Section: Resultsmentioning

confidence: 99%

Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

et al. 2022

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“…In fact, the protein concentrations used in this study mirrored previous experimental approaches used in cell culture assays to assess the biological activity of the recombinant proteins (Serna et al, 2019;Carratalá et al, 2020a;Carratalá et al, 2020c;Álamo et al, 2020). The soluble version and the IBs format of T22-GFP-H6 have been tested for the selective interaction with CXCR4+ cells to target metastatic cells in a variety of cancer types as well as their performance as an antimicrobial agent due to the presence of the T22 peptide (polyphemusin) isolated from the hemocytes of horseshoe crabs (Céspedes et al, 2016;Falgàs et al, 2020a;Falgàs et al, 2020b;Céspedes et al, 2020;Serna et al, 2021). The IFN-γ proteins, in both formats, have been assayed in cultured cells and in animal models to check the immunostimulatory effect of the cytokine in infectious diseases (Carratalá et al, 2020a;Carratalá et al, 2020c).…”

Section: Discussionmentioning

confidence: 99%

Toxicity Profiling of Bacterial Inclusion Bodies in Human Caco-2 Cells

Barguilla

Unzueta

Carratalá

et al. 2022

Front. Bioeng. Biotechnol.

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Bacterial inclusion bodies (IBs) are discrete macromolecular complexes that appear in recombinant prokaryotic cells under stress conditions. These structures are often discarded for biotechnological uses given the difficulty in recovering proteins of interest from them in a soluble form. However, recent approaches have revealed the potential of these protein clusters as biomaterials to promote cell growth and as protein depots for the release of recombinant proteins for biotechnological and biomedical applications. Although these kinds of natural supramolecular complexes have attracted great interest, no comprehensive study of their toxicity in cell cultures has been carried out. In this study, caco-2 cells were exposed to natural IBs, soluble protein-only nanoparticles (NPs), and non-assembled versions of the same protein for comparative purposes. Cytotoxicity, oxidative stress, and genotoxicity were analyzed for all these protein formats. Natural IBs and soluble protein formats demonstrated their safety in eukaryotic cells. No cytotoxicity, genotoxicity, or oxidative stress was detected in caco-2 cells exposed to the protein samples in any of the experimental conditions evaluated, which covered protein concentrations used in previous biological activity assays. These conditions evaluated the activity of protein samples obtained from three prokaryotic hosts [Escherichia coli and the endotoxin-free expression systems Lactococcus lactis and ClearColi® BL21 (DE3)]. Our results demonstrate that natural IBs and soluble protein nanoparticles are non-toxic materials for eukaryotic cells and that this may represent an interesting alternative to the classical unassembled format of recombinant proteins for certain applications in biotechnology and biomedicine.

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“…This finding is important not only because microbial infections can occur after tumor diffusion, but also because they can contribute to tumor formation. T22 can then exert a dual role as a CXCR4 antagonist targeting the downstream pathways in tumors overexpressing this receptor and as an antimicrobial agent [ 77 ].…”

Section: Cxcr4 Antagonistsmentioning

confidence: 99%

Targeting CXCR4 and CD47 Receptors: An Overview of New and Old Molecules for a Biological Personalized Anticancer Therapy

Leo

Sabatino

2022

IJMS

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Biological therapy, with its multifaceted applications, has revolutionized the treatment of tumors, mainly due to its ability to exclusively target cancer cells and reduce the adverse effects on normal tissues. This review focuses on the therapies targeting the CXCR4 and CD47 receptors. We surveyed the results of early clinical trials testing compounds classified as nonpeptides, small peptides, CXCR4 antagonists or specific antibodies whose activity reduces or completely blocks the intracellular signaling pathways and cell proliferation. We then examined antibodies and fusion proteins against CD47, the receptor that acts as a “do not eat me” signal to phagocytes escaping immune surveillance. Despite these molecules being tested in early clinical trials, some drawbacks are emerging that impair their use in practice. Finally, we examined the ImmunoGenic Surrender mechanism that involves crosstalk and co-internalization of CXCR4 and CD47 upon engagement of CXCR4 by ligands or other molecules. The favorable effect of such compounds is dual as CD47 surface reduction impact on the immune response adds to the block of CXCR4 proliferative potential. These results suggest that a combination of different therapeutic approaches has more beneficial effects on patients’ survival and may pave the way for new accomplishments in personalized anticancer therapy.

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Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

Cited by 7 publications

References 121 publications

Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

Toxicity Profiling of Bacterial Inclusion Bodies in Human Caco-2 Cells

Targeting CXCR4 and CD47 Receptors: An Overview of New and Old Molecules for a Biological Personalized Anticancer Therapy

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