A Potent Leukocyte Transmigration Blocker: GT-73 Showed a Protective Effect against LPS-Induced ARDS in Mice.
Molecules
; 26(15)2021 Jul 29.
Article
in English
| MEDLINE | ID: covidwho-1346516
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-1ß, 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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pyrimidines
/
Respiratory Distress Syndrome
/
Platelet Endothelial Cell Adhesion Molecule-1
/
Transendothelial and Transepithelial Migration
/
COVID-19 Drug Treatment
/
Leukocytes
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Animals
/
Female
/
Humans
Language:
English
Journal subject:
Biology
Year:
2021
Document Type:
Article
Affiliation country:
Molecules26154583
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