TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization
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Published:2023-06-05
Issue:6
Volume:10
Page:117-132
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ISSN:2311-2638
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Container-title:Microbial Cell
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language:
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Short-container-title:Microb Cell
Author:
Thierry Sylvain,Maadadi Sarah,Berton Aurore,Dimier Laura,Perret Clémence,Vey Nelly,Ourfali Saïd,Saccas Mathilde,Caron Solène,Boucard-Jourdin Mathilde,Colombel Marc,Werle Bettina,Bonnin Marc
Abstract
Toll-like receptor 3 (TLR3) is an innate immune receptor that recognizes double-stranded RNA (dsRNA) and induces inflammation in immune and normal cells to initiate anti-microbial responses. TLR3 acts also as a death receptor only in cancer cells but not in their normal counterparts, making it an attractive target for cancer therapies. To date, all of the TLR3-activating dsRNAs used at preclinical or clinical stages have major drawbacks such as structural heterogeneity, toxicity, and lack of specificity and/or efficacy. We conducted the discovery process of a new family of TLR3 agonists that are chemically manufactured on solid-phase support and perfectly defined in terms of sequence and size. A stepwise discovery process was performed leading to the identification of TL-532, a 70 base pair dsRNA that is potent without transfection reagent and is highly specific for TLR3 without activating other innate nucleic sensors such as RIG-I/MDA5, TLR7, TLR8, and TLR9. TL-532 induces inflammation in murine RAW264.7 myeloid macrophages, in human NCI-H292 lung cancer cells, and it promotes immunogenic apoptosis in tumor cells in vitro and ex vivo without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.
Publisher
Shared Science Publishers OG
Subject
Biochemistry, Genetics and Molecular Biology (miscellaneous),Molecular Biology,Cell Biology,Genetics,Microbiology,Parasitology,Virology,Applied Microbiology and Biotechnology
Cited by
4 articles.
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