# Inhibition of GSDMD as a new treatment for infection

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $183,035

## Abstract

Sepsis plagues 19 million per year globally, with a mortality rate of ~ 30%, resulting in ~ five million
deaths every year. Sepsis is caused by a dysregulated host response to infection. Over reaction
of the immune system upon detection of the invasion of microbes triggers inflammatory reaction,
the excessive reaction of which eventually lead to multiple organ failure and patient death.
Pyroptosis is a form of programmed cell death in the immune response signaling pathway during
infection. The detection of microbe invasion triggers the activation of the inflammatory caspases,
which cleaves the linker between the N-terminal (NT) and C-terminal (CT) domains of the effector
protein gasdermin D (GSDMD). This cleavage lifts the auto-inhibition of the GSDMD CT domain
on the NT domain, which subsequently binds to the inner leaflet of the cell membrane,
oligomerizes, and forms pores that are large enough for inflammatpry cytokines such as IL-1β to
be released and trigger downstream responses. Studies have shown that GSDMD is the sole and
direct effector of pyroptosis, and deletion of the GSDMD gene significantly improved the survival
rate in a murine sepsis model. Therefore, we hypothesize that small molecule inhibitors that
disrupt GSDMD function can effectively alleviate negative effects of pyroptosis on septic
patient, and thus improve the outcome of sepsis treatment. To search for GSDMD inhibitors,
we will pursue three specific aims to develop assays and validate them through screening a small
collection of compounds. Aim 1. To develop an assay to identify compounds that strengthen
GSDMD auto-inhibition. Aim 2. To develop an assay to identify compounds that prevent GSDMD
interaction and pore-forming in membrane. Aim 3. To screen a small collection of compounds to
validate and optimize assays. In preliminary studies, we established that the GSDMD is a
tractable target. In addition, we have engineered several GSDMD constructs and developed
several novel methods and primitive assays, which established the feasibility of the proposed
approach. Outcomes of the proposed study include the establishment of useful assays for HTS
and identification of a collection of active compound structures. In the next stage at the conclusion
of this exploratory/developmental R21 project, we will seek additional funding and collaboration
to test a larger number of compounds and develop medicinal chemistry and biology components
to further test and develop identified compounds. It is our expectation that novel classes of
inhibitors binding to original target sites on GSDMD to prevent its pore-forming activity will be
identified, which will lead to the development of new anti-infection therapeutics.

## Key facts

- **NIH application ID:** 9817680
- **Project number:** 5R21AI142063-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Yinan Wei
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $183,035
- **Award type:** 5
- **Project period:** 2018-11-05 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9817680

## Citation

> US National Institutes of Health, RePORTER application 9817680, Inhibition of GSDMD as a new treatment for infection (5R21AI142063-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9817680. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*