A potent leukocyte transmigration blocker: Gt-73 showed a protective effect against lps-induced ards in mice

Eliav Blum, Raanan Margalit, Laura Levy, Tamar Getter, Ron Lahav, Sofia Zilber, Paul Bradfield, Beat A. Imhof, Evgenia Alpert, Arie Gruzman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4583
JournalMolecules
Volume26
Issue number15
DOIs
StatePublished - 29 Jul 2021

Keywords

  • ARDS
  • Covalent inhibitor
  • Cytokine storm
  • Leukocyte transmigration
  • PECAM-1

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Physical and Theoretical Chemistry
  • Pharmaceutical Science
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'A potent leukocyte transmigration blocker: Gt-73 showed a protective effect against lps-induced ards in mice'. Together they form a unique fingerprint.

Cite this