Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A (PLA) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA. Recently, varespladib was also found to inhibit snake venom PLA and PLA-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA and PLA-like toxins.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.biochi.2022.11.006 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Elucidating on the Quaternary Structure of Viper Venom Phospholipase A Enzymes in Aqueous Solution.
Biochimie
January 2025
LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal. Electronic address:
This study focuses on the quaternary structure of the viper-secreted phospholipase A (PLA), a central toxin in viper envenomation. PLA enzymes catalyse the hydrolysis of the sn-2 ester bond of membrane phospholipids. Small-molecule inhibitors that act as snakebite antidotes, such as varespladib, are currently in clinical trials.
View Article and Find Full Text PDFCorrigendum to "In vitro anticoagulant effects of Bungarus venoms on human plasma which are effectively neutralized by the PLA2-inhibitor varespladib" [Toxicon Volume 252, December 2024, 108178].
Toxicon
January 2025
Ophirex, Inc., Corte Madera, CA, 94925, USA; California Academy of Sciences, San Francisco, CA, 94118, USA. Electronic address:
A genus-wide study on venom proteome variation and phospholipase A inhibition in Asian lance-headed pit vipers (genus: Trimeresurus).
Comp Biochem Physiol C Toxicol Pharmacol
February 2025
Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; School of Medicine, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan; Institute of Bioinformatics and Structural Biology, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:
Article Synopsis
- The research utilized techniques like SDS-PAGE and LCMS/MS to investigate venom protein variability and identified conserved protein families with diverse expressions that do not follow snake evolutionary lineages.
- Key findings indicate that while certain enzymes' expression correlates weakly with venom effects, phospholipase A activity strongly correlates with its abundance, and a small molecule inhibitor, varespladib, may effectively inhibit PLA activities, suggesting its potential as a therapeutic for snakebite treatment.
In vitro anticoagulant effects of Bungarus venoms on human plasma which are effectively neutralized by the PLA-inhibitor varespladib.
Toxicon
December 2024
Ophirex, Inc., Corte Madera, CA, 94925, USA; California Academy of Sciences, San Francisco, CA, 94118, USA. Electronic address:
Bungarus (krait) envenomings are well-known for their life-threatening neurotoxic effects. However, their impact on coagulation remains largely unexplored experimentally or clinically. This study, examined the effect of begins to examine venoms from four Bungarus species-B.
View Article and Find Full Text PDFHigh expression of PLA2G2A in fibroblasts plays a crucial role in the early progression of carotid atherosclerosis.
J Transl Med
October 2024
The Clinical Systems Biology Laboratories of the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, 450052, Henan, China.
Article Synopsis
- In mouse models, knocking out the PLA2G2A gene reduces atherosclerotic plaque volume, but clinical trials with the sPLA2 inhibitor Varespladib haven’t effectively lowered cardiovascular risk, highlighting the need for further research on PLA2G2A's mechanisms.
- Using single-cell transcriptome data from carotid plaques with patient info, researchers found that PLA2G2A is mainly expressed in vascular fibroblasts and interacts significantly with macrophages, especially in early plaque stages related to inflammation.
- The study concludes that PLA2G2A promotes early plaque progression by activating macrophage-related pathways and suggests its serum levels could be valuable for diagnosing mild carotid artery stenosis.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!