19 research outputs found
Novel hydrazine molecules as tools to understand the flexibility of vascular adhesion protein-1 ligand-binding site: toward more selective inhibitors
O-sulfated bacterial polysaccharides with low anticoagulant activity inhibit metastasis
Heparin-like polysaccharides possess the capacity to inhibit cancer cell
proliferation, angiogenesis, heparanase-mediated cancer cell invasion,
and cancer cell adhesion to vascular endothelia via adhesion receptors,
such as selectins. The clinical applicability of the antitumor effect of
such polysaccharides, however, is compromised by their anticoagulant
activity. We have compared the potential of chemically O-sulfated and
N,O-sulfated bacterial polysaccharide (capsular polysaccharide from E. coli
K5 [K5PS]) species to inhibit metastasis of mouse B16-BL6 melanoma
cells and human MDA-MB-231 breast cancer cells in two in vivo models. We
demonstrate that in both settings, O-sulfated K5PS was a potent
inhibitor of metastasis. Reducing the molecular weight of the
polysaccharide, however, resulted in lower antimetastatic capacity.
Furthermore, we show that O-sulfated K5PS efficiently inhibited the
invasion of B16-BL6 cells through Matrigel and also inhibited the in
vitro activity of heparanase. Moreover, treatment with O-sulfated K5PS
lowered the ability of B16-BL6 cells to adhere to endothelial cells,
intercellular adhesion molecule-1, and P-selectin, but not to
E-selectin. Importantly, O-sulfated K5PSs were largely devoid of
anticoagulant activity. These findings indicate that O-sulfated K5PS
polysaccharide should be considered as a potential antimetastatic agent.</p
Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis
Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1)
Blockage of Collagen Binding to Integrin alpha2beta1: Structure-activity Relationships of Protein-protein Interaction Inhibitors
The interaction between the alpha2beta1
integrin and collagen plays a crucial role in the development of pathological
conditions, such as thrombus formation and cancer cell metastasis. Accordingly,
the alpha2beta1 integrin is a promising target for the development of new drug
molecules to treat these diseases. Here, we have designed, synthesized, and
measured in vitro a set of novel drug-like compounds that block the protein–protein
interactions between alpha2beta1 integrin and collagen. The obtained
structure–activity relationship reveals the key features that are required for
successful inhibition of this integrin–collagen interaction.</p
Identification of Two Imidazole Binding Sites and Key Residues for Substrate Specificity in Human Primary Amine Oxidase AOC3
Novel alpha 2 beta 1 Integrin Inhibitors Reveal That Integrin Binding to Collagen under Shear Stress Conditions Does Not Require Receptor Preactivation
The interaction between alpha 2 beta 1 integrin (GPIa/IIa, VLA-2) and vascular collagen is one of the initiating events in thrombus formation. Here, we describe two structurally similar sulfonamide derivatives, BTT-3033 and BTT-3034, and show that, under static conditions, they have an almost identical effect on alpha 2-expressing CHO cell adhesion to collagen I, but only BTT-3033 blocks platelet attachment under flow (90 dynes/cm(2)). Differential scanning fluorimetry showed that both molecules bind to the alpha 2I domain of the recombinant alpha 2 subunit. To further study integrin binding mechanism(s) of the two sulfonamides, we created an alpha 2 Y285F mutant containing a substitution near the metal ion-dependent adhesion site motif in the alpha 2I domain. The action of BTT-3033, unlike that of BTT-3034, was dependent on Tyr-285. In static conditions BTT-3034, but not BTT3033, inhibited collagen binding by an alpha 2 variant carrying a conformationally activating E318W mutation. Conversely, in under flow conditions (90 dynes/cm(2)) BTT-3033, but not BTT-3034, inhibited collagen binding by an alpha 2 variant expressing E336A loss-of-function mutation. Thus, the binding sites for BTT-3033 and BTT-3034 are differentially available in distinct integrin conformations. Therefore, these sulfonamides can be used to study the biological role of different functional stages of alpha 2 beta 1. Furthermore, only the inhibitor that recognized the nonactivated conformation of alpha 2 beta 1 integrin under shear stress conditions effectively blocked platelet adhesion, suggesting that the initial interaction between integrin and collagen takes place prior to receptor activation