A Potent Leukocyte Transmigration Blocker: GT-73 Showed a Protective Effect against LPS-Induced ARDS in Mice.

Tytuł:: A Potent Leukocyte Transmigration Blocker: GT-73 Showed a Protective Effect against LPS-Induced ARDS in Mice.
Autorzy:: Blum E; Department of Chemistry, Faculty of Exact Sciences, Campus Ramat-Gan, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Margalit R; Science in Action, 3 Pinchas Sapir Street, Weizmann Science Park, Ness-Ziona 7403650, Israel.
Levy L; Department of Chemistry, Faculty of Exact Sciences, Campus Ramat-Gan, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Getter T; Department of Chemistry, Faculty of Exact Sciences, Campus Ramat-Gan, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Lahav R; AltA-ZuZ Therapeutics, 3 Pinchas Sapir Street, Weizmann Science Park, Ness-Ziona 7403650, Israel.
Zilber S; Department of Pathology, Shaare Zedek Medical Center, 12 Shmuel Bait Street, Jerusalem 9103102, Israel.
Bradfield P; MesenFlow Technologies, Chemin des Aulx, 14, CH-1228 Geneva, Switzerland.
Imhof BA; Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet, CH-1211 Geneva, Switzerland.
Alpert E; AltA-ZuZ Therapeutics, 3 Pinchas Sapir Street, Weizmann Science Park, Ness-Ziona 7403650, Israel.
Gruzman A; Department of Chemistry, Faculty of Exact Sciences, Campus Ramat-Gan, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Źródło:: Molecules (Basel, Switzerland) [Molecules] 2021 Jul 29; Vol. 26 (15). Date of Electronic Publication: 2021 Jul 29.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basel, Switzerland : MDPI, c1995-
MeSH Terms:: COVID-19 Drug Treatment*
Leukocytes/*drug effects
Platelet Endothelial Cell Adhesion Molecule-1/*antagonists & inhibitors
Pyrimidines/*pharmacology
Respiratory Distress Syndrome/*drug therapy
Transendothelial and Transepithelial Migration/*drug effects
Animals ; COVID-19/pathology ; Cell Adhesion/drug effects ; Cell Adhesion/immunology ; Cell Movement/drug effects ; Cytokine Release Syndrome/drug therapy ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Humans ; Leukocytes/immunology ; Lipopolysaccharides/adverse effects ; Mice ; Mice, Inbred BALB C ; Platelet Endothelial Cell Adhesion Molecule-1/immunology ; Pyrimidines/chemistry ; Respiratory Distress Syndrome/chemically induced ; SARS-CoV-2
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Grant Information:: 182009 Bar-Ilan University new faculty grant
Contributed Indexing:: Keywords: ARDS; PECAM-1; covalent inhibitor; cytokine storm; leukocyte transmigration
Substance Nomenclature:: 0 (Cytokines)
0 (Lipopolysaccharides)
0 (Platelet Endothelial Cell Adhesion Molecule-1)
0 (Pyrimidines)
Entry Date(s):: Date Created: 20210807 Date Completed: 20210813 Latest Revision: 20230920
Update Code:: 20240105
PubMed Central ID:: PMC8348436
DOI:: 10.3390/molecules26154583
PMID:: 34361736
: Czasopismo naukowe

Pełny tekst

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.

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