# Screening for inhibitors of allergen-associated airway smooth muscle contraction

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $218,750

## Abstract

PROJECT SUMMARY
Despite aggressive treatment with high-dose inhaled corticosteroids plus bronchodilators, approximately 5-10%
of people with asthma (15-30 million) experience severe and life-threatening symptoms of bronchoconstriction.
Nearly one-half of these severe asthma patients are also “sensitized” (i.e. have IgE mediated allergy) to common
molds such as Aspergillus fumigatus (Af). This condition has now been recognized as a distinct entity and
designated fungal asthma (FA). Unfortunately, current therapies for FA—antifungals and/or omalizumab (anti-
IgE)—have not proven to be efficacious in the long-term.
By studying Af-induced bronchoconstriction in mice and people with asthma, our team has discovered a novel,
direct, and druggable target in FA—the Af allergen-derived serine protease, alkaline protease 1 (Alp1). Alp1
promotes the defining symptom of FA—bronchoconstriction—by inducing airway smooth muscle (ASM)
contraction, through mechanisms that appear to be independent of allergic inflammation. In this application, we
will pursue the hypothesis that inhibitors of Alp1-induced human ASM contraction can be discovered by high
throughput screening (HTS). In aim 1, we will use HTS to identify small molecular inhibitors of Alp1 protease. In
aim 2, we will examine the effects of FA pathobiology on the efficacy of Alp1-inhibitor therapy. In aim 3, we will
determine mechanism and examine significance for Alp1-inhibitor therapy. We expect our approach to identify
novel anti-FA drug candidates, and in doing so, offer substantial insight into both ASM-intrinsic and allergen
protease dependent mechanisms of bronchoconstriction.

## Key facts

- **NIH application ID:** 10176398
- **Project number:** 5R21AI151695-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** RAMASWAMY KRISHNAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,750
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176398

## Citation

> US National Institutes of Health, RePORTER application 10176398, Screening for inhibitors of allergen-associated airway smooth muscle contraction (5R21AI151695-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10176398. Licensed CC0.

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