A Potent Leukocyte Transmigration Blocker: GT-73 Showed a Protective Effect against LPS-Induced ARDS in Mice
Open Access
- 29 July 2021
- Vol. 26 (15), 4583
- https://doi.org/10.3390/molecules26154583
Abstract
We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert-butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties (tert-butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1β, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.Funding Information
- Bar-Ilan University new faculty grant (182009)
This publication has 32 references indexed in Scilit:
- RETRACTED: Endothelial PECAM-1 and its function in vascular physiology and atherogenic pathologyExperimental and Molecular Pathology, 2016
- Prevention of LPS-Induced Acute Lung Injury in Mice by ProgranulinMediators of Inflammation, 2012
- Neutrophil Transmigration Mediated by the Neutrophil-Specific Antigen CD177 Is Influenced by the Endothelial S536N Dimorphism of Platelet Endothelial Cell Adhesion Molecule-1The Journal of Immunology, 2010
- Activation and Regulation of Systemic Inflammation in ARDSSocial psychiatry. Sozialpsychiatrie. Psychiatrie sociale, 2009
- Cytokines, Inflammation, and PainInternational Anesthesiology Clinics, 2007
- The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapyCancer Biology & Therapy, 2006
- PECAM-1–dependent neutrophil transmigration is independent of monolayer PECAM-1 signaling or localizationBlood, 2003
- Expression of Cytokines in Bacterial and Viral Infections and Their Biochemical AspectsThe Journal of Biochemistry, 2000
- Antibodies Against the First Ig-Like Domain of Human Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) That Inhibit PECAM-1-Dependent Homophilic Adhesion Block In Vivo Neutrophil RecruitmentThe Journal of Immunology, 2000
- Changes in expression of the cell adhesion molecule PECAM‐1 (CD31) during differentiation of human leukemic cell linesTissue Antigens, 1994