# Targeting F-box protein 048 in acute lung injury

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Acute lung injury (ALI) is a devastating disorder among Veterans commonly occurring after
sepsis or severe pneumonia. Two key manifestations of ALI are a fundamental inability to
extract oxygen and inflammation, both of which may have a mitochondrial basis. Although
ALI subjects have mitochondrial defects, the molecular mechanisms underlying their injury
that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic
basis of this proposal resides on our discovery of a unique molecular model of mitochondrial
injury whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger
inflammation by mediating degradation of a crucial cytoprotective, anti-inflammatory energy
sensor, 5′-AMP-activated protein kinase (AMPK). By targeting the C-terminal molecular
signature present in Fbxo48, we designed, synthesized, and tested a novel small molecule,
BC-1618, that stabilizes AMPK levels, preserves mitochondrial function, and reduces
inflammation in murine and human ALI models. Thus, in this application we will first elucidate
how a common pathogen, S. aureus, depletes AMPK through Fbxo48, thereby accentuating
experimental ALI (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its
degradation using complementary in vitro and in vivo genetic models, including
CRISPR/Cas9 Fbxo48 knockout mice. Next we will examine the pharmacokinetic and
pharmacodynamics properties of BC-1618 focusing on its mitochondrial-protective and anti-
inflammatory properties in ALI models (Aim 2). A unique approach in this application is
execution of small molecule testing in an ex vivo human lung perfusion system. These
studies will provide a new pathobiologic model of mitochondrial injury that will serve as a
platform for presenting the first-in-class dual acting small molecule modulator that optimizes
cellular bioenergetics and limits inflammation in subjects with severe critical illness.

## Key facts

- **NIH application ID:** 10683699
- **Project number:** 5I01CX000105-09
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Toru Nyunoya
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683699

## Citation

> US National Institutes of Health, RePORTER application 10683699, Targeting F-box protein 048 in acute lung injury (5I01CX000105-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10683699. Licensed CC0.

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