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Published in Chad A. Mirkin, Spherical Nucleic Acids, 2020
Aleksandar F. Radovic-Moreno, Natalia Chernyak, Christopher C. Mader, Subbarao Nallagatla, Richard S. Kang, Liangliang Hao, David A. Walker, Tiffany L. Halo, Timothy J. Merkel, Clayton H. Rische, Sagar Anantatmula, Merideth Burkhart, Chad A. Mirkin, Sergei M. Gryaznov
Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
Assessment of Quercetin Isolated from Enicostemma Littorale Against Few Cancer Targets: An in Silico Approach
Published in A. K. Haghi, Ana Cristina Faria Ribeiro, Lionello Pogliani, Devrim Balköse, Francisco Torrens, Omari V. Mukbaniani, Applied Chemistry and Chemical Engineering, 2017
Toll-like receptor 7 also known as TLR7 is an immune gene possessed by humans and other mammals. The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on SCC, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung, placenta and spleen, and lies in close proximity to another family member.43
RNAi as New Class of Nanomedicines
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Monika Dominska, Derek M. Dykxhoorn
Innate immune responses function as a mechanism to recognize and eliminate pathogens, while aiding in the establishment of adaptive immunity. This recognition requires a diverse family of pattern recognition receptors to detect a variety of bacterial and viral-associated molecules, such as, lipopolysaccharides, bacterial DNA, and viral RNAs [77, 78]. Originally, siRNAs were believed to be unable to engage the RNA-dependent protein kinase (PKR) pathway due to their small size (<30bp) [38]. However, more recent studies have shown that, in some cases, synthetic siRNAs could stimulate aspects of the innate immune response through the engagement of Toll-like receptors (TLRs), in particular, TLR7 and TLR8 [68, 79, 132]. It has been suggested that the sequence-independent engagement of TLR3 on dendritic cells and endothelial cells could be a source of additional toxicity [80, 133]. However, TLR3 signaling does not appear to be a major determinant of innate immune activation by siRNAs. On the other hand, the sequence-specific engagement of TLR7 and TLR8 seems to be the primary mechanism for the induction of innate immune activation by synthetic siRNAs [28, 46, 64]. Both TLR7 and TLR8 are expressed in the endosomes and their signaling requires endosomal acidification. Although similar in function and intracellular localization, they are expressed in different subsets of cells, with TLR7 predominating in plasmacytoid dendritic cells and B cells, while TLR8 expression is restricted to dendritic cells, monocytes and macrophages. Although the immunostimulatory effects of siRNAs have not been fully characterized, it appears that these receptors recognize GU-rich RNA sequences [28, 64, 68, 79]. Selecting siRNAs that avoid these GU-rich motifs can help to reduce the immunostimulatory nature of certain siRNAs [79]. However, GU-rich sequences alone can’t account for the full range of siRNA immunogenicity. While GU-rich sequences have been shown to engage TLR7 and TLR8, AU-rich sequences were found to preferentially activate TLR8 [46]. Additional factors, including the position of immunostimulatory motifs within the siRNA, sequence context, and the length of the siRNA molecule, have been suggested to influence the immunostimulatory nature of siRNAs [54, 68].
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
Stimulating antiviral effector cells: Toll-like receptors (TLRs) are a family of membrane-bound pattern recognition receptors that play an important role in both innate and adaptive immune responses through interactions with pathogen-associated molecular patterns. TLR-7 is activated in plasma dendritic cells, leading to production of interferon-alpha (IFN-α), which has direct antiviral properties through induction of ISGs and also indirect antiviral properties through inhibition of cccDNA transcription. TLR-7 also upregulates activation of both natural killer (NK) cells and HBV-specific B lymphocytes. The first oral TLR-7 agonist vesatolimod (GS-9620) demonstrated potent antiviral activity in woodchucks and chimpanzees with sustained HBV DNA suppression and HBsAg loss and reduction in rate of HCC development (Menne et al. 2015). In clinical studies however, patients who received vesatolimod for 12 weeks demonstrated dose-dependent pharmacodynamic induction of ISG15 without systemic IFN-α production. However, these were not accompanied with meaningful changes in HBsAg or HBV DNA levels (Agarwal et al. 2018; Janssen et al. 2018). Results from other oral TLR-7 agonists in clinical development are awaited (RO7020531; JNJ-4964).