ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • Register
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 1813

Novel Mechanism of Action of Anti-Malarial Drugs in the Inhibition of Type I Interferon Production

Jie An1, Joshua Woodward2, Mark Minie3, YuFeng Peng4, Tomikazu Sasaki5 and Keith B. Elkon6, 1Division of Rheumatology, Department of Medicine & Immunology, University of Washington, Seattle, WA, 2Department of Microbiology, University of Washington, Seattle, WA, 3Department of Bioengineering, University of Washington, Seattle, WA, 4Rheumatology, University of Washington, Seattle, WA, 5Department of Chemistry, University of Washington, Seattle, WA, 6Department of Medicine & Immunology, University of Washington, Seattle, WA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Antimalarial drugs, innate immunity, interferons and toll-like receptors, SLE

  • Tweet
  • Email
  • Print
Save to PDF
Session Information

Date: Monday, November 9, 2015

Session Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment Poster Session II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Anti-malarial drugs (AMD) such as Hydroxychloroquine (HCQ) and Quinacrine (QC) are effective in the treatment of skin rash and arthritis in systemic lupus erythematosus (SLE). AMD have multiple modes of action, but precisely which mechanism(s) are responsible for their beneficial action is uncertain. Type I interferon, (IFN-I) is strongly implicated in the pathogenesis of SLE as well as rare monogenic ‘interferonopathies’ such as Aicardi-Goutieres Syndrome (AGS). Recently, a new DNA activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), was discovered and linked to AGS. To identify potential inhibitors of the DNA-cGAS interaction, we performed in silico screening of chemical and drug libraries.

Methods: In silico structure-based drug screening were provided by the CANDO docking algorithm. Predictions made by CANDO were confirmed by Autodock Vina and analyzed via PyMOL. cGAS activity/cGAMP production was analyzed by Thin Layer Chromatography (TLC). DNA-binding to cGAS in the presence or absence of AMD was determined by Electrophoretic Mobility Shift Assay (EMSA). Following DNA cell transfections, cytokines were quantified by qPCR, ELISA or an ISRE-luciferase reporter assay.

Results: In silico screening of chemical and drug libraries identified several antimalarial drugs (AMD) including HCQ, QC, Chloroquine (CQ), Primaquine (PQ) and 9-amino-6-chloro-2-methoxyacridine (ACMA), which could potentially inhibit cGAS activity by interacting with the cGAS/DNA dimer complex. These AMD inhibited cGAS activity/cGAMP production in a dose dependent manner. Interestingly, the in silico predicted binding affinities of these AMD correlated well with their potency (QC>ACMA>HCQ>CQ>PQ) to inhibit cGAS activity, validating the prediction of our computational analysis. EMSA revealed that AMD disrupted the double stranded DNA-cGAS complex in a dose dependent manner, indicating that AMD blocked dsDNA/cGAS binding. These AMD also inhibited IFN-I expression in THP1 cells transfected with dsDNA and in 293T cells transfected with cGAS/STING plasmids validating that cGAS is a target of AMD. Based on these results and in silico modeling, we synthesized several new AMD. One of these compounds, X6, had excellent water solubility and cell penetration. Fluorescence microscopy revealed that X6 localized to the cytosol and had a lower toxicity profile compared to QC. In vitro and cell based studies, revealed that X6 was a more potent inhibitor of IFN-I production following dsDNA transfection into reporter cells than HCQ. X6 was also more potent than HCQ in the inhibition of IFN-a production following CpGA stimulation of PBMC.

Conclusion: Our studies identify the cytosolic DNA sensor, cGAS, as a target of AMD activity, which provide a novel mechanism of action of these AMD. This observation together with decades of experience of AMD in human diseases, suggest that this widely used family of drugs with a strong safety profile could be repurposed to target interferonopathies and possibly other autoimmune disorders related to cGAS over-activity.


Disclosure: J. An, None; J. Woodward, None; M. Minie, None; Y. Peng, None; T. Sasaki, None; K. B. Elkon, None.

To cite this abstract in AMA style:

An J, Woodward J, Minie M, Peng Y, Sasaki T, Elkon KB. Novel Mechanism of Action of Anti-Malarial Drugs in the Inhibition of Type I Interferon Production [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/novel-mechanism-of-action-of-anti-malarial-drugs-in-the-inhibition-of-type-i-interferon-production/. Accessed February 28, 2021.
  • Tweet
  • Email
  • Print
Save to PDF

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-mechanism-of-action-of-anti-malarial-drugs-in-the-inhibition-of-type-i-interferon-production/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Convergence: Where Rheumatology Meets. All Virtual. November 5-9.

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2021 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
loading Cancel
Post was not sent - check your email addresses!
Email check failed, please try again
Sorry, your blog cannot share posts by email.
This site uses cookies: Find out more.