Arylboronic acids inhibit P2X7 receptor function and the acute inflammatory response
Robson Xavier Faria1,2, Noemi de Jesus Hiller3, Juliana Pimenta Salles4
1Laboratory of Toxoplasmosis and Other Protozoans, Instituto Oswaldo Cruz, Avenida Brasil, 4365, Pavilion 108, room 32, CEP, Rio de Janeiro, Fiocruz, 21045-900, Brazil. salvador@ioc.fiocruz.br.
Journal of Bioenergetics and Biomembranes
|July 1, 2019
Summary
Researchers identified novel boronic acid derivatives, NO-01 and NO-12, that effectively inhibit the P2X7 receptor (P2X7R). Compound NO-01 shows significant potential as a lead structure for developing new anti-inflammatory drugs targeting P2X7R.
Area of Science:
- Pharmacology
- Molecular Biology
- Medicinal Chemistry
Background:
- The P2X7 receptor (P2X7R) is an ATP-gated ion channel implicated in inflammatory processes.
- P2X7R is a recognized therapeutic target for anti-inflammatory drug development.
Purpose of the Study:
- To evaluate a series of eight boronic acid analogs for their biological effects on human and murine P2X7R.
- To identify potent P2X7R inhibitors with anti-inflammatory potential.
Main Methods:
- In vitro assays measuring P2X7R function, dye uptake, and IL-1β release.
- In vivo assessment of ATP-induced paw edema.
- Molecular docking simulations to predict binding interactions.
Main Results:
- Boronic acid derivatives NO-01 and NO-12 demonstrated significant inhibition of human and murine P2X7R function.
- NO-01 and NO-12 outperformed BBG and were comparable to A740003 in inhibiting dye uptake, IL-1β release, and edema.
- Molecular docking indicated that NO derivatives bind to the P2X7 pore, with key interactions involving hydrophobic and hydrogen bonds with specific residues.
Conclusions:
- The boronic acid derivative NO-01 emerged as the lead compound from this series.
- NO-01 exhibits characteristics suitable for a scaffold structure in the development of novel P2X7R inhibitors for anti-inflammatory applications.
Related Concept Videos
01:28Inflammatory Response
16.1K
An inflammatory response is a localized, nonspecific immune reaction that occurs when a tissue is injured. It is characterized by redness, swelling, heat, and pain, which are commonly called the cardinal signs and symptoms of inflammation. Inflammation can sometimes result in a loss of function.
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...
16.1K
01:24Inflammatory Response II: Inflammatory Exudate and Tissue Repair
7.5K
The immune system's inflammatory response destroys the invading pathogen, permitting the tissue to heal. The changes during the cellular and vascular stages allow exudate formation at the site of inflammation. The inflammatory exudate released from the wound has high protein content and a specific gravity above 1.020.
The typical wound exudate is odorless, transparent, straw-colored, thin, and watery. Exudate, however, can differ depending on the state of wound healing. Likewise, the...
The typical wound exudate is odorless, transparent, straw-colored, thin, and watery. Exudate, however, can differ depending on the state of wound healing. Likewise, the...
7.5K
01:30Inflammatory Response I: Vascular and Cellular
16.2K
The inflammatory response is the body's defense against infection, injury, or irritation from bacteria, trauma, toxins, or heat. Inflammation helps locate and destroy pathogens and remove damaged tissue elements to heal the body. During this initial phase, fluid, blood products, and nutrients migrate to the injured area, resulting in redness, heat, swelling, ache, and loss of function. Moreover, signs of systemic inflammation include fever, increased WBC count, malaise, anorexia, nausea,...
16.2K
00:46Feedback Inhibition
56.9K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
56.9K
01:31Internal Receptors
74.3K
Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
74.3K
01:19Composition of Polyprotic Acid Solutions as a Function of pH
837
Polyprotic acids of the type H2M constitute two ionizable protons. As a result, on titration with a base, they exhibit two equivalence points in the titration curve. During titration, the species H2M, HM−, and M2− will be present in the solution at different points. The fractions of H2M, HM−, and M2− present at the various instances of the titration are denoted by α0, α1, and α2, respectively.
A graph with the alpha values is plotted against the volume of...
A graph with the alpha values is plotted against the volume of...
837