Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

Adair, Brian D.; Alonso, José L.; Agthoven, Johannes van; Hayes, Vincent; Ahn, Hyun Sook; Yu, I-Shing; Lin, Shu‐Wha; Xiong, Jian-Ping; Poncz, Mortimer; Arnaout, M. Amin

doi:10.1038/s41467-019-13928-2

Cited by 41 publications

(36 citation statements)

References 70 publications

(66 reference statements)

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“…Ligands in the blood such as fibrinogen (and other proteins) bind to integrin αIIbβ3 receptors, and bridge activated platelets. 4–6 This leads to platelet aggregation and the formation of a platelet plug that prevents bleeding from a damaged vessel. 7–11 Secondary hemostasis occurs concurrently with primary hemostasis and involves the activation of factors in intrinsic and extrinsic pathways of the coagulation cascade.…”

Section: Introductionmentioning

confidence: 99%

Tantalum-containing mesoporous bioactive glass powder for hemostasis

et al. 2020

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This study evaluates the hemostatic properties of tantalum-containing mesoporous bioactive glasses (Ta-MBGs) through a suite of in-vitro methods: hemolysis percentage, zeta potential, blood coagulation assays (Activated Partial Thromboplastin Time – APTT and Prothrombin Time - PT) and cytotoxicity tests. Five compositions of Ta-MBG, with x mol% Ta2O5 added to the glass series (80- x)SiO2-15CaO-5P2O5- xTa2O5 where x=0 (0Ta), x=0.5 (0.5Ta), x=1 (1Ta), x=5 (5Ta), and x=10 (10Ta) mol%, were synthesised. The hemostatic potential of all the Ta-MBGs was confirmed by their negative zeta potential (–23 to –31 mV), which enhances the intrinsic pathway of blood coagulation. The hemolysis percentages of all Ta-MBGs except 10Ta showed statistically significant reductions compared to the same experiments carried out both in the absence of a sample (‘no treatment’ group) and in the presence of 10Ta. These observations validate the consideration of Ta-MBGs as hemostatic agents as they do not cause significant lysis of red blood cells. Cytotoxicity analysis revealed that Ta-MBGs had no effect on bovine fibroblast viability. Furthermore, a reduction in both APTT (a test to evaluate the intrinsic pathway of coagulation) and PT (a test to evaluate the extrinsic pathway) signified enhancement of hemostasis: 5Ta caused a significant reduction in APTT compared to ‘no treatment’, 1Ta and 10Ta and a significant reduction in PT compared to 0Ta. Therefore, we conclude that 5mol% of Ta optimised the hemostatic properties of these mesoporous bioactive glasses.

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Section: Introductionmentioning

confidence: 99%

Tantalum-containing mesoporous bioactive glass powder for hemostasis

et al. 2020

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“…The histogram in Fig. 1 shows the expression level of integrins on the surface of human melanoma cells, M21 using specific antibodies [7].…”

Section: Integrin Cell Surface Levelmentioning

confidence: 99%

“…We used the following model cells derived from the same cell line: M21, expressing avb3 and a5b1; M21L, expressing only a5b1; and M21GPIIb, expressing aIIbb3 and a5b1, but not avb3 [7]. Cells were grown on surfaces without specific coating and/or with fibronectin, and the elasticity was probed using atomic force microscopy to answer the following questions: The results from these measurements were compared with previous stiffness measurements of the same cell lines using a microfluidic device under non-adherent cellular conditions [8].…”

Section: Introductionmentioning

confidence: 99%

αvβ3 integrin expression increases elasticity in human melanoma cells

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Goldmann

et al. 2020

Biochemical and Biophysical Research Communications

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Integrin avb3 a5b1 and aIIbb3 M21 human melanoma cell Atomic force microscopy Micro-constrictions Cell elasticity a b s t r a c t Living cells interact with the extracellular matrix (ECM) transducing biochemical signals into mechanical cues and vice versa. Thanks to this mechano-transduction process, cells modify their internal organization and upregulate their physiological functions differently. In this complex mechanism integrins play a fundamental role, connecting the extracellular matrix with the cytoskeleton. Cytoskeletal rearrangements, such as the increase of the overall contractility, impact cell mechanical properties, the entire cell stiffness, and cell deformability. How cell mechanics is influenced via different integrins and their interaction with ECM in health and disease is still unclear. Here, we investigated the influence of avb3 integrin expression on the mechanics of human melanoma M21 cells using atomic force microscopy and micro-constriction. Evidence is provided that (i) avb3 integrin expression in human melanoma cells increases cell stiffness in both adherent and non-adherent conditions; (ii) replacing avb3 with aIIbb3 integrin in melanoma cells, cell stiffness is increased under adherent, while decreased under nonadherent conditions; (iii) avb3 integrin cell stiffening is also maintained when cells adhere to fibronectin, but this phenomenon does not strongly depend on the fibronectin concentration. In all, this study sheds light on the role of avb3 in regulating cellular mechanics.

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“…Moreover, RGD‐like compounds may behave as true agonists mimicking the ECM natural ligand‐dependent activation of integrins and subsequent pro‐tumoral signaling pathways [41] . Very interestingly, recent developments on integrin pure antagonists have been published supporting a new area in integrin ligand research [81–84] . Based on electron microscopy, X‐ray crystallography and receptor priming studies, it was shown that these new classes of integrin antagonists do not induce the integrin conformational changes associated with activation.…”

Section: Rgd‐integrin Ligandsmentioning

confidence: 99%

Biological Relevance of RGD‐Integrin Subtype‐Specific Ligands in Cancer

et al. 2020

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Integrins are heterodimeric transmembrane proteins able to connect cells with the micro‐environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg‐Gly‐Asp (RGD) peptide in their natural extracellular matrix ligands have been particularly investigated as tumoral therapeutic targets. In the last 30 years, intense research has been dedicated to designing specific RGD‐like ligands able to discriminate selectively the different RGD‐recognizing integrins. Chemists′ efforts have led to the proposition of modified peptide or peptidomimetic libraries to be used for tumor targeting and/or tumor imaging. Here we review, from the biological point of view, the rationale underlying the need to clearly delineate each RGD‐integrin subtype by selective tools. We describe the complex roles of RGD‐integrins (mainly the most studied αvβ3 and α5β1 integrins) in tumors, the steps towards selective ligands and the current usefulness of such ligands. Although the impact of integrins in cancer is well acknowledged, the biological characteristics of each integrin subtype in a specific tumor are far from being completely resolved. Selective ligands might help us to reconsider integrins as therapeutic targets in specific clinical settings.

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Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

Cited by 41 publications

References 70 publications

Tantalum-containing mesoporous bioactive glass powder for hemostasis

Tantalum-containing mesoporous bioactive glass powder for hemostasis

αvβ3 integrin expression increases elasticity in human melanoma cells

Biological Relevance of RGD‐Integrin Subtype‐Specific Ligands in Cancer

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