Method of treatment

An amino acid and sequence technology, applied in chemical instruments and methods, pharmaceutical formulations, animal/human proteins, etc., can solve problems such as antibody elevation and ability deficiency

Pending Publication Date: 2020-07-14
ROYAL MELBOURNE INST OF TECH +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Notably, mice chronically deficient in NOX2 oxidase have an increased tendency to develop autoantibodies (Campbell et al. (2012) Science Translational Medicine 4(157):157ra141), and patients with chronic granulomatous disease develop ROS capacity is defective with elevated circulating type I IFN and autoantibodies (Kelkka et al. (2014) Antioxidants & Redox Signaling 21(16):2231-2245)

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0192] Influenza virus drives endosomal ROS

[0193] To address the potential role of endosomal ROS production in viral pathology, influenza A viruses, which belong to group IV anti-strand ssRNA viruses of the Orthomyxoviridae family and are internalized by endocytosis, were first considered. Dose and time of exposure of mouse alveolar macrophages (AM), mouse peritoneal RAW264.7 cells, or bone marrow-derived macrophages (BMDM) to influenza A virus strain HKx31(H3N2) resulting in influenza nucleoprotein (NP) fluorescence The dependent increase, which was nearly abolished by the potent dynamin inhibitor, Dynasore (100M), suggests a clathrin-coated pit or caveolin-dependent internalization mechanism. Internalizing viruses showed strong co-localization with the early endosomal marker EEA1 (Fig. 1a). However, not all NPs co-localized with EEA1, suggesting that influenza A virus is not only present in early endosomes (Fig. 1a), but may have entered late endosomes and / or lysosomes. ...

Embodiment 2

[0195] Endosomal TLR7-NOX2 signaling axis

[0196] RNA viruses are endosomally TLR7 (for ssRNA viruses) [Lund et al. (2004) Proceedings of the National Academy of Sciences of the United States of America 101 (15): 5598-5603, Diebold et al. Science 303 (5663): 1529- 1531] and TLR3 (dsRNA virus), and the cytoplasmic sensor retinoic acid-inducible gene I (RIG-1) (which can detect viral RNA with a 5' triphosphate (Lund et al. (2004) supra) and NOD-like receptors NLRs [Iwasaki and Pillai (2014) supra; Ichinohe et al. (2009) The Journal of Experimental Medicine 206(1):79-87; Allen et al. (2009) Immunity 30(4):556-565]. It is hypothesized that influenza A enters acidified endosomes, leading to the release of viral RNA, the activation of TLR7, and the stimulation of NOX2 oxidase-dependent ROS production. Consistent with this suggestion, TLR7 associates with influenza A (Fig. 2a), NOX2 (Fig. 2b) co-localizes with EEA1 (Fig. 2c), from TLR7 - / - Primary AMs of mice and TLR7- and MyD88-d...

Embodiment 3

[0199] Strain independence of endosomal ROS

[0200] Macrophages exposed to rhinovirus (picornaviridae, group IV), respiratory syncytial virus (paramyxoviridae, group V), human parainfluenza virus (paramyxoviridae, V group), human metapneumovirus (paramyxoviridae, group V), Sendai virus (paramyxoviridae, group V), dengue virus (flavoviridae, group IV) or HIV (retroviridae, group VI, ssRNA-RT viruses) lead to a marked increase in endosomal ROS, which is expressed in TLR7 - / - significantly suppressed in macrophages, but not in TLR9 - / - cells were not affected (Figure 3a and Figure 3b). Neither mumps virus (paramyxoviridae, group V) nor Newcastle disease virus (NDV, paramyxoviridae, group V) produced significant endosomal ROS (Fig. Note that these viruses primarily enter cells through the process of membrane fusion rather than endocytosis. Exposure of macrophages to rotavirus (rhesus strain or bovine UK strain, (reoviridae, group III)) also did not produce endosomal ROS (Fig....

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Abstract

The present invention relates generally to the field of immunomodulation. Taught herein is an agent for inhibiting immunostimulation mediated by a Toll-like receptor useful in the treatment of viral and microbial pathogenesis, diseases involving elements of autoimmunity and inflammation as well as cancer. The agent antagonizes disulfide bond formation between C98 and C475 of Toll-like receptor 7 (TLR7) thereby preventing TLR7 activation.Pharmaceutical compositions are also enabled herein.

Description

[0001] This application is related to and claims priority from Australian Provisional Patent Application No. 2017902545, entitled "A Method of Treatment", filed 30 June 2017, the entire contents of which are incorporated herein by reference. This specification refers to a Sequence Listing. The "ST25.txt" file is in ANSI format. This document is hereby incorporated by reference in its entirety from AU2017902545 into this specification. technical field [0002] The present invention relates generally to the field of immunomodulation. Agents for inhibiting immune stimulation mediated by Toll-like receptors are taught herein, which are useful in the treatment of viral and microbial diseases, diseases involving autoimmune and inflammatory elements, and cancer. Also realized herein are pharmaceutical compositions. Background technique [0003] Bibliographic details for the publications cited by the authors in this specification are collected alphabetically at the end of this sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/08A61P35/00A61P37/00A61K38/16C07K7/00C07K14/00A61P31/00A61P29/00
CPCA61P31/00A61P29/00A61P35/00A61P37/00C07K2319/10C07K14/705A61K38/177A61K38/00C07K7/06C07K14/70596
Inventor S·塞勒米迪斯D·A·布鲁克斯J·欧莱里
Owner ROYAL MELBOURNE INST OF TECH
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