Delving into the Latest Updates on A-967079 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

TRPA1

Action

inhibitors

Mechanism

TRPA1 inhibitors(Transient receptor potential cation channel subfamily A member 1 inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Pain

Originator Organization

Abbott Laboratories

Active Organization-

Inactive Organization

Abbott LaboratoriesUniversity of Aalborg

License Organization-

Drug Highest PhasePendingClinical

First Approval Date-

Regulation-

Enterovirus D68 (EV-D68) has had several outbreaks worldwide, yet no FDA-approved antiviral is available for treating this viral infection. EV-D68 infection typically leads to respiratory illnesses and, in severe cases, can cause neurological complications and even death, particularly in children. This study identified a small molecule, A-967079, as an EV-D68 antiviral through phenotypical screening. A-967079 has shown potent and broad-spectrum antiviral activity with a high selectivity index against multiple strains of EV-D68. Pharmacological characterization of the mechanism of action involving time-of-addition, resistance selection, and differential scanning fluorimetry assays suggests that viral 2C protein is the drug target. Overall, A-967079 represents a promising candidate for further development as an EV-D68 antiviral.

01 Nov 2024·LARYNGOSCOPE

Transient Receptor Potential Ankyrin 1 Channel Alters Transforming Growth Factor Beta 1/Smad Signaling in Rat Vocal Fold Fibroblasts

Article

Author: Mukudai, Shigeyuki ; Sugiyama, Yoichiro ; Hashimoto, Keiko ; Matsushita, Hiroki ; Kaneko, Mami ; Branski, Ryan C. ; Hirano, Shigeru

Objectives:

Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor‐beta 1 (TGF‐β1)‐mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF‐β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF‐β1/Smad signaling in VFFs.

Methods:

Vocal folds were dissected from 10‐week‐old, male Sprague‐Dawley rats and primary VFFs were established. TRPA1 was examined in VFFs and lamina propria via immunostaining. VFFs were treated with allyl isothiocyanate (AITC, TRP channel agonist, 10−5 M) ± TGF‐β1 (10 ng/ml) ± A‐967079 (selective TRPA1 channel antagonist, 5.0 × 10−7 M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR.

Results:

TRPA1 was expressed in cultured VFFs and the lamina propria. TGF‐β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF‐β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF‐β1 alone; A‐967079 significantly reduced this response.

Conclusions:

VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF‐β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti‐fibrotic mechanisms of TRPA1 activation through TGF‐β1/Smad signaling in VFFs.

Level of Evidence:

NA Laryngoscope, 134:4593–4598, 2024

01 Mar 2024·The Science of the total environment

TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury

Article

Author: Feng, Yi ; Zhang, Hai ; Li, Mengnan ; Liu, Qi ; Wang, Xiaohui ; Weng, Jiali ; Mao, Ruolin ; Chung, Kian Fan ; Yang, Xiaohua ; Li, Chenfei ; Chang, Qing ; Zhang, Na ; Huang, Yan ; Adcock, Ian M ; Li, Feng ; Xie, Meiqin

BACKGROUND:

Transient receptor potential (TRP) ankyrin 1 (TRPA1) could mediate ozone-induced lung injury. Optic Atrophy 1 (OPA1) is one of the significant mitochondrial fusion proteins. Impaired mitochondrial fusion, resulting in mitochondrial dysfunction and ferroptosis, may drive the onset and progression of lung injury. In this study, we examined whether TRPA1 mediated ozone-induced bronchial epithelial cell and lung injury by activating PI3K/Akt with the involvement of OPA1, leading to ferroptosis.

METHODS:

Wild-type, TRPA1-knockout (KO) mice (C57BL/6 J background) and ferrostatin-1 (Fer-1)-pretreated mice were exposed to 2.5 ppm ozone for 3 h. Human bronchial epithelial (BEAS-2B) cells were treated with 1 ppm ozone for 3 h in the presence of TRPA1 inhibitor A967079 or TRPA1-knockdown (KD) as well as pharmacological modulators of PI3K/Akt-OPA1-ferroptosis. Transcriptome was used to screen and decipher the differential gene expressions and pathways. Oxidative stress, inflammation and ferroptosis were measured together with mitochondrial morphology, function and dynamics.

RESULTS:

Acute ozone exposure induced airway inflammation and airway hyperresponsiveness (AHR), reduced mitochondrial fusion, and enhanced ferroptosis in mice. Similarly, acute ozone exposure induced inflammatory responses, altered redox responses, abnormal mitochondrial structure and function, reduced mitochondrial fusion and enhanced ferroptosis in BEAS-2B cells. There were increased mitochondrial fusion, reduced inflammatory responses, decreased redox responses and ferroptosis in ozone-exposed TRPA1-KO mice and Fer-1-pretreated ozone-exposed mice. A967079 and TRPA1-KD enhanced OPA1 and prevented ferroptosis through the PI3K/Akt pathway in BEAS-2B cells. These in vitro results were further confirmed in pharmacological modulator experiments.

CONCLUSION:

Exposure to ozone induces mitochondrial dysfunction in human bronchial epithelial cells and mouse lungs by activating TRPA1, which results in ferroptosis mediated via a PI3K/Akt/OPA1 axis. This supports a potential role of TRPA1 blockade in preventing the deleterious effects of ozone.

100 Deals associated with A-967079

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