Novel inhibitors of leukocyte transendothelial migration

Getter, Tamar; Margalit, Raanan; Kahremany, Shirin; Levy, Laura M.; Blum, Eliav; Khazanov, Netali; Keshet-Levy, Nimrod Y.; Tamir, Tigist Y.; Major, Michael B.; Lahav, Ron; Zilber, Sophia; Senderowitz, Hanoch; Bradfield, Paul F.; Imhof, Beat A.; Alpert, Evgenia; Gruzman, Arie

doi:10.1016/j.bioorg.2019.103250

Cited by 23 publications

(21 citation statements)

References 82 publications

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“…In our previous publication, we reported the screening results (the blocking of leukocyte transendothelial migration) of a series of lipophilic compounds [ 10 ]. We carefully studied the structural differences between the nonblocking (GT-77) and the completely blocking (GT-73) compounds [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

“…We recently developed a potent inhibitor of leukocyte transmigration from the blood to the tissues (GT-73). This compound was also able to increase the reverse transmigration of monocytes [ 10 ]. Compound GT-73, based on the scaffolding of barbituric acid, has already shown highly promising results as a drug candidate for the treatment of other inflammatory and autoimmune disorders (e.g., Crohn’s disease, multiple sclerosis, fatty liver disease, inflammatory bowel disease, and rheumatoid arthritis).…”

Section: Introductionmentioning

confidence: 99%

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

Blum

Margalit²,

Levy

et al. 2021

Molecules

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Blum

Margalit²,

Levy

et al. 2021

Molecules

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“… 28 MG-induced upregulation of key proteins such as ezrin, integrin β-1, Ras-related protein Rap-1b, transforming protein RhoA, Thy-1 membrane glycoprotein, and vascular cell adhesion protein 1 and downregulation of 72 kDa type IV collagenase, which are involved in leukocyte transendothelial migration, form an important step in eliciting inflammatory immune response. 29 MT1-MMP-dependent shedding of CD44 plays a key role in regulation of leukocyte adhesion to the pancreatic blood vessels and the transendothelial migration of diabetogenic, cytotoxic T cells into the islet cells. 30 This was also associated with enrichment of proteins involved in complement and coagulation cascades such as complement C3, α-2-macroglobulin, and urokinase-type plasminogen activator that were upregulated and proteins such as complement C1s subcomponent, clusterin, vitamin K-dependent protein S, and plasminogen activator inhibitor 1 were downregulated in MG-induced secretome.…”

Section: Results and Discussionmentioning

confidence: 99%

CD44, a Predominant Protein in Methylglyoxal-Induced Secretome of Muscle Cells, is Elevated in Diabetic Plasma

et al. 2020

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Methylglyoxal (MG), a glycolytic intermediate and reactive dicarbonyl, is responsible for exacerbation of insulin resistance and diabetic complication. In this study, MG-induced secretome of rat muscle cells was identified and relatively quantified by SWATH-MS. A total of 643 proteins were identified in MG-induced secretome, of which 82 proteins were upregulated and 99 proteins were downregulated by more than 1.3-fold in SWATH analysis. Further, secretory proteins from the classical secretory pathway and nonclassical secretory pathway were identified using SignalP and SecretomeP, respectively. A total of 180 proteins were identified with SignalP, and 113 proteins were identified with SecretomeP. The differentially expressed proteins were functionally annotated by KEGG pathway analysis using Cytoscape software with plugin clusterMaker. The differentially expressed proteins were found to be involved in various pathways like extracellular matrix (ECM)–receptor interaction, leukocyte transendothelial migration, fluid shear stress and atherosclerosis, complement and coagulation cascades, and lysosomal pathway. Since the MG levels are high in diabetic conditions, the presence of MG-induced secreted proteins was inspected by profiling human plasma of healthy and diabetic subjects ( n = 10 each). CD44, a predominant MG-induced secreted protein, was found to be elevated in the diabetic plasma and to have a role in the development of insulin resistance.

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“…Myosin light chain 2 (MLC2) phosphorylation plays pivotal roles in actin/myosin motor activation to provide essential contractile forces for several cellular processes, such as cell contraction, cytokinesis, cell migration and membrane blebbing (Duan et al, 2016; Jiang et al, 2014). Leukocyte transendothelial migration is one of the most important steps in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases of mice (Getter et al, 2019). The protein directly interacting with MLC2‐1 was MYH6_7 (myosin heavy chain 6/7) in the sub‐network (Figure 7b and Table 6).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals immune‐related differentially expressed genes in the hepatopancreas and gills of Penaeus vannamei after Vibrio anguillarum infection

Song

Soomro

et al. 2021

Aquaculture Research

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Penaeus vannamei is one of the commercially important aquaculture species in the world but sensitive to Vibrio anguillarum infection. To understand the immune response of P. vannamei against V. anguillarum infection, the transcriptomes of hepatopancreas and gills of P. vannamei were analysed before and after V. anguillarum infection. Total 6213 differentially expressed genes (DEGs) were obtained from the hepatopancreas, and 3780 were obtained from the gills. The DEGs of interest were screened to construct a heat map. The reliability and accuracy of the transcriptome data were verified using RT‐qPCR. HSP70 and ARF6 were found highly expressed in both hepatopancreas and gills, while MLC2s encoded by two different gene sequences were found to be expressed in hepatopancreas and gills. Six immune‐related DEGs were identified from the protein–protein interaction (PPI) network including the HSP70, ARF6 and MLC2s. The sub‐network of PPI was constructed to explore the mode of interaction of immune‐related DEGs with their neighbouring proteins. Based on the result of PPI network, we infer that phosphorylated MLC2‐1 conducts signal transduction to induce leukocyte transendothelial migration in P. vannamei gills tissue while MLC2‐2 plays a role in immunity of V. anguillarum infection not only through activating signal transduction to mediate immune responses but also through the formation of phagosomes in hepatopancreas tissue. HSP70 is associated with the transporting exogenous cargos through presenting antigenic peptides in the process of V. anguillarum infection in P. vannamei. ARF6 interacts with Rab proteins to regulate phagolysosome formation by regulating GTPase activity in P. vannamei gills tissue. In hepatopancreas tissue, ARF6 plays a role in immunity by interacting with cytohesin. This study will contribute to further exploring the immune mechanism of P. vannamei to V. anguillarum infection.

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Novel inhibitors of leukocyte transendothelial migration

Cited by 23 publications

References 82 publications

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

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

CD44, a Predominant Protein in Methylglyoxal-Induced Secretome of Muscle Cells, is Elevated in Diabetic Plasma

Transcriptome analysis reveals immune‐related differentially expressed genes in the hepatopancreas and gills of Penaeus vannamei after Vibrio anguillarum infection

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