# Development of antagonists targeting STING in systemic lupus erythematosus

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $186,754

## Abstract

Project Summary
Stimulator of interferon genes (STING) is a cytosolic endoplasmic reticulum anchored receptor protein involved
in the propagation of innate immune sensing of cytosolic DNA through the production of Interferon-ß (IFN-ß).
Mechanistic studies have shown IFN-ß production within a tumor microenvironment can result in activation of
tumor antigen-specific CD8+ T-cell immunity that can lead to tumor regression. STING activation by STING
agonists should result in innate T-cell mediated anti-tumor immunity in the tumor microenvironment and have
significant potential as a cancer therapeutic. Conversely, we hypothesize that: inhibition of STING will lead to a
decreased production of IFN-ß which will reduce the immune response to cytosolic DNA and RNA and thereby
reduce life-threatening conditions in systemic lupus erythematosus (SLE). Molecular Dynamics (MD)
equilibrated crystal structures for human HAQ, REF, and wild type (WT) STING alleles were clustered to find
optimal conformations for computational chemical library screening via computational docking utilizing rigid
receptor, induced fit, and quantum polarized ligand models. Models for both STING agonists and antagonists
were developed. A novel low-molecular-weight organic molecule that is not based on a cyclic dinucleotide
(such as STING’s normal ligand, 2’,3’-cyclic-GAMP) was found as a strong binder of STING. The compound
was synthesized in our laboratory and its structure was confirmed using LC/MS and 1H and 13C NMR. Proteins
representing both the HAQ and WT alleles (representing 78.3% of the human population) were tested against
our compound with 2’,3’-cGAMP and DMSO as positive and negative controls, respectively in a luciferase
reporter model. In short, pIRF-3 (the immediate downstream protein activated by STING) was measured by
luminescence in THP-1 monocytic leukemic cells and gave a signal for the luminescence of luciferin that was
approximately 100 fold weaker than 2’,3’-cGAMP. Moreover, in Surface Plasmon Resonance (SPR)
experiments we determined that our compound possesses a KD of ~400nM. We hypothesize that our
compound is a partial agonist that can be converted to a full antagonist using iterative rounds of computational
modeling, synthesis, and experimental testing.
We are designing analogs of this compound as potential antagonists of STING for SLE therapy. The strong
binding of the compound will be preserved while exploring R group modifications that can suppress the STING
pathway for SLE. It is noteworthy that antagonists of STING are anticipated to play a strong role in ameliorating
life threatening conditions in SLE. What is needed are confirmatory experiments that our lead compound can
be optimized as a STING antagonist that will be effective in SLE. We are employing our expertise in
computational drug discovery, synthetic and medicinal chemistry, biophysical binding measurements, and in
vitro cell-based assays, to perform “lead exploration” studies that will result ...

## Key facts

- **NIH application ID:** 9877280
- **Project number:** 1R21AI149450-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Wayne Guida
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,754
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877280

## Citation

> US National Institutes of Health, RePORTER application 9877280, Development of antagonists targeting STING in systemic lupus erythematosus (1R21AI149450-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9877280. Licensed CC0.

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