更新于：2024-11-01

BPIFA1 x ORAI1

更新于：2024-11-01

基本信息

关联

项与 BPIFA1 x ORAI1 相关的药物

ELD-607

靶点

BPIFA1 x ORAI1

作用机制

BPIFA1 stimulators [+1]

在研机构

Eldec Pharmaceuticals, Inc.

原研机构

Eldec Pharmaceuticals, Inc.

在研适应症

肠杆菌感染 [+5]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 BPIFA1 x ORAI1 相关的临床结果

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100 项与 BPIFA1 x ORAI1 相关的转化医学

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0 项与 BPIFA1 x ORAI1 相关的专利（医药）

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项与 BPIFA1 x ORAI1 相关的文献（医药）

2024-11-01·Cell Calcium

ELD607 specifically traffics Orai1 to the lysosome leading to inhibition of store operated calcium entry

Article

作者: Wrennall, Joe A ; Tarran, Robert ; Flori Sassano, M ; Goriounova, Alexandra S

Orai1 is a plasma membrane Ca²⁺ channel involved in store operated calcium entry (SOCE). SOCE can regulate cell growth, exocytosis, gene expression and inflammation. We previously found that short palate lung and nasal epithelial clone 1's (SPLUNC1) sixth α-helix (α6) bound Orai1 to inhibit SOCE. SPLUNC1 was not proteolytically stable, so we developed ELD607, an 11 amino acid peptide based on SPLUNC1's α6 region which was more stable and more potent than SPLUNC1/α6. Here, we studied ELD607's mechanism of action. We overexpressed either Orai1-HA or Orai1-YFP in HEK293T cells to probe ELD607-Orai1 interactions by confocal microscopy. We also measured changes in Fluo-4 fluorescence in a multiplate reader as a marker of cytoplasmic Ca²⁺ levels. ELD607 internalized Orai1 independently of STIM1. Both 15 min and 3 h exposure to ELD607 similarly depleted Orai1 in the plasma membrane. However, 3 h exposure to ELD607 yielded greater inhibition of SOCE. ELD607 continued to colocalize with Orai1 after internalization and this process was dependent on the presence of the ubiquitin ligase NEDD4.2. Similarly, ELD607 increased the colocalization between Orai1 and ubiquitin. ELD607 also increased the colocalization between Orai1 and Rab5 and 7, but not Rab11, suggesting that Orai1 trafficked through early and late but not recycling endosomes. Finally, ELD607 caused Orai1, but not Orai2, Orai3, or STIM1 to traffic to lysosomes. We conclude that ELD607 rapidly binds to Orai1 and works in an identical fashion as full length SPLUNC1 by internalizing Orai1 and sending it to lysosomes, leading to a decrease in SOCE.

2022-05-01·Physiological Reports

SPLUNC1 is a negative regulator of the Orai1 Ca²⁺ channel

Article

作者: Goriounova, Alexandra S. ; Ahmad, Saira ; Flori Sassano, M. ; Wu, Tongde ; Worthington, Erin N. ; Tarran, Robert ; Wrennall, Joe A. ; Ghosh, Arunava

AbstractOrai1 is a ubiquitously‐expressed plasma membrane Ca2+ channel that is involved in store‐operated Ca2+ entry (SOCE): a fundamental biological process that regulates gene expression, the onset of inflammation, secretion, and the contraction of airway smooth muscle (ASM). During SOCE, Ca2+ leaves the endoplasmic reticulum, which then stimulates a second, amplifying wave of Ca2+ influx through Orai1 into the cytoplasm. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1; gene name BPIFA1) is a multi‐functional, innate defense protein that is highly abundant in the lung. We have previously reported that SPLUNC1 was secreted from epithelia, where it bound to and inhibited Orai1, leading to reduced SOCE and ASM relaxation. However, the underlying mechanism of action is unknown. Here, we probed the SPLUNC1‐Orai1 interactions in ASM and HEK293T cells using biochemical and imaging techniques. We observed that SPLUNC1 caused a conformational change in Orai1, as measured using Forster resonance energy transfer (FRET). SPLUNC1 binding also led to Nedd4‐2 dependent ubiquitination of Orai1. Moreover, SPLUNC1 internalized Orai1 to lysosomes, leading to Orai1 degradation. Thus, we conclude that SPLUNC1 is an allosteric regulator of Orai1. Our data indicate that SPLUNC1‐mediated Orai1 inhibition could be utilized as a therapeutic strategy to reduce SOCE.

2022-03-01·American Journal of Respiratory Cell and Molecular Biology1区 · 医学

A SPLUNC1 Peptidomimetic Inhibits Orai1 and Reduces Inflammation in a Murine Allergic Asthma Model

1区 · 医学

Article

作者: Ghosh, Arunava ; Voeller, Alexis S. ; Hickey, Anthony J. ; Tarran, Robert ; Sassano, M. Flori ; Krajewski, Krzysztof ; Worthington, Erin N. ; Stewart, Ian E. ; Wu, Tongde ; Goriounova, Alexandra S. ; Tilley, Steven L. ; Wrennall, Joe A. ; Ahmad, Saira

Orai1 is a plasma membrane Ca²⁺ channel that mediates store-operated Ca²⁺ entry (SOCE) and regulates inflammation. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is an asthma gene modifier that inhibits Orai1 and SOCE via its C-terminal α6 region. SPLUNC1 levels are diminished in asthma patient airways. Thus, we hypothesized that inhaled α6 peptidomimetics could inhibit Orai1 and reduce airway inflammation in a murine asthma model. To evaluate α6-Orai1 interactions, we used fluorescent assays to measure Ca²⁺ signaling, Förster resonance energy transfer, fluorescent recovery after photobleaching, immunostaining, total internal reflection microscopy, and Western blotting. To test whether α6 peptidomimetics inhibited SOCE and decreased inflammation in vivo, wild-type and SPLUNC1^-/- mice were exposed to house dust mite (HDM) extract with or without α6 peptide. We also performed nebulization, jet milling, and scanning electron microscopy to evaluate α6 for inhalation. SPLUNC1^-/- mice had an exaggerated response to HDM. In BAL-derived immune cells, Orai1 levels increased after HDM exposure in SPLUNC1^-/- but not wild-type mice. Inhaled α6 reduced Orai1 levels in mice regardless of genotype. In HDM-exposed mice, α6 dose-dependently reduced eosinophilia and neutrophilia. In vitro, α6 inhibited SOCE in multiple immune cell types, and α6 could be nebulized or jet milled without loss of function. These data suggest that α6 peptidomimetics may be a novel, effective antiinflammatory therapy for patients with asthma.