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Publications (9)26.25 Total impact

  • Ewald M. Aydt · Daniel Bock · Gerhard Wolff ·
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    ABSTRACT: Selectin antagonists comprise a heterogeneous group of synthetic molecules, natural product compounds and biologics. They are targeted against the selectin family of cell adhesion molecules (selectins), which are located on the surface of endothelial cells (E- and P-selectin), platelets (P-selectin) and of leukocytes (L-selectin). Selectins play a crucial role in the adhesion and activation of leukocytes and platelets in inflammation. They are supposed to be involved in the pathogenesis of several respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Selectin antagonists targeting one, two or all three selectins (panselectin antagonists) were developed. Depending on the target binding site, sialyl Lewis X (sLe X)-mimicking antagonists can be distinguished from antagonists mimicking more complex natural ligand structures like, for example, P-selectin glycoprotein ligand-1 (PSGL-1). To date, the most advanced pan-selectin antagonist in development is Bimosiamose mimicking both sLe X and PSGL-1. It has been demonstrated to be effective in animal models of inflammatory lung diseases and human clinical trials for asthma and COPD. Based on the preclinical and clinical experiences with Bimosiamose, this chapter summarizes the potential impact of selectin antagonists for the treatment of inflammatory lung diseases.
    Progress in Respiratory Research 09/2010; 39. DOI:10.1159/000320817
  • Ewald M Aydt · Gerhard Wolff · Ingo Morano ·
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    ABSTRACT: Type II myosin is the molecular motor which drives contraction upon cyclic interaction with filamentous actin while consuming ATP. The contemporary crystallographic structure of the myosin subfragment-1 (S1) of myosin covers both the motor domain of the heavy chain (MHC) as well as the essential (ELC) and regulatory light chains (RLC). A part of the N-terminus of the ELC is, however, missing in the 3D-models of Type II myosin. The N-terminal domain of the ELC comprises interesting functional features since it binds to actin thus controlling myosin motor activity. For the first time, we modeled the missing 46 N-terminal amino acid of the ELC to the contemporary actin-myosin-S1 complex. We show a rod-like 91 A structure being long enough to bridge the gap between the ELC core of myosin-S1 and the appropriate binding site of the ELC on the actin filament.
    Journal of Structural Biology 08/2007; 159(1):158-63. DOI:10.1016/j.jsb.2007.04.002 · 3.23 Impact Factor

  • Journal of Molecular and Cellular Cardiology 06/2007; 42(6). DOI:10.1016/j.yjmcc.2007.03.288 · 4.66 Impact Factor
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    ABSTRACT: The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation. Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV(1)) data were recorded and nasopharyngeal examinations were performed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of bimosiamose. All subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multiple-dose study after inhalation of bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml(-1)) only at doses > or =50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml(-1) was determined for the AUC over the entire period of treatment of the multiple-dose study. The results suggest that single and multiple inhalation of bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.
    British Journal of Clinical Pharmacology 05/2007; 63(4):451-8. DOI:10.1111/j.1365-2125.2006.02775.x · 3.88 Impact Factor
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    ABSTRACT: This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.
    Journal of Medicinal Chemistry 04/2007; 50(6):1101-15. DOI:10.1021/jm060536g · 5.45 Impact Factor
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    Journal of Molecular and Cellular Cardiology 03/2007; DOI:10.1016/j.yjmcc.2007.03.892 · 4.66 Impact Factor
  • Daniel Bock · Ewald M. Aydt · Wolfgang M. Kuebler · Gerhard Wolff ·
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    ABSTRACT: The selectin family of cell adhesion molecules (selectins) is comprised of three structurally related calciumdependent carbohydrate binding proteins, E-, P-, and L-selectin. Located on the surface of endothelial cells (E- and Pselectin), platelets (P-selectin) and of leucocytes (L-selectin), selectins are of vital importance for leukocyte recruitment and accumulation in the vasculature. Based on the unique architecture of the microvasculature of the lung, this task is achieved by two different types of selectin mediated functions (i) tethering and rolling of leukocytes on the pre- and post capillary pulmonary endothelium and in bronchial venules which are mediated by E-, P-, and L-selectin as well as (ii) retention of leukocytes in the pulmonary capillaries by L-selectin. Recent findings in preclinical and clinical research suggest a significant involvement of selectins in both acute and chronic inflammatory lung diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), asthma bronchiale (Asthma), chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). This review summarizes the current progress in understanding the role of selectins during inflammation in the lung and its potential impact for innovative therapeutic strategies.
    Current Respiratory Medicine Reviews 07/2006; 2(3):339-354. DOI:10.2174/157339806778018953
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    ABSTRACT: The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients. In vitro bimosiamose proved to be inhibitory to E- or P-selectin dependent lymphocyte adhesion under flow conditions. Using xenogeneic transplantation models, bimosiamose reduced disease severity as well as development of psoriatic plaques in symptomless psoriatic skin. The administration of bimosiamose in patients suffering from psoriasis resulted in a reduction of epidermal thickness and lymphocyte infiltration. The clinical improvement was statistically significant (P=0.02) as analyzed by comparison of psoriasis area and severity index before and after treatment. Assessment of safety parameters showed no abnormal findings. These data suggest that pan-selectin antagonism may be a promising strategy for the treatment of psoriasis and other inflammatory diseases.
    Archives for Dermatological Research 03/2006; 297(8):345-51. DOI:10.1007/s00403-005-0626-0 · 1.90 Impact Factor
  • Aydt EM · Gerhard Wolff ·
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    ABSTRACT: Asthma is characterized by chronic inflammation of large and small airways maintained by extravasation of leukocytes from the bloodstream into the surrounding peribronchial tissue. The process of extravasation is of crucial importance in inflammation and is mediated by a sequenced and concerted action between different adhesion molecules on endothelial cells and ligands on leukocytes. In this context, initial rolling and tethering is generally considered to be the primary event which is mediated by selectins, a family of glycoproteins comprised of E-, P- and L-selectin. Their role in asthma has been demonstrated in a variety of animal models, showing that all three selectins are involved in the chronic inflammation in asthma. Therefore, selectins are an attractive target where pan-selectin antagonism is the desired treatment strategy. Here, we give an overview of the status of the preclinical and clinical development of bimosiamose, the most advanced synthetic pan-selectin antagonist as a treatment for asthma.
    Pathobiology 01/2002; 70(5):297-301. DOI:10.1159/000070746 · 2.48 Impact Factor