In the present study we will investigate the role of heparanase in the pathogenesis of Antiphospholipid Syndrome (APS), implementing a rational drug design approach to discover and develop new drug compounds such as heparanase inhibitors. Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity. It is well known that in these patients thrombosis may be the result of a hypercoagulable state related to anti-beta2-glycoprotein I (beta2-GPI) antibodies. We recently demonstrated that anti-beta2-GPI antibodies trigger a signal transduction pathway leading to TF expression, the major initiator of the clotting cascade in human platelets, monocytes and endothelial cells.
Thus, this research project is developed in 3 main objectives:
1. Analysis of heparanase activity in sera of APS patients and relationship with clinical features and active arterial thrombosis;
2. Analysis of the role of heparanase in the signal transduction pathway triggered by anti-beta2-GPI antibodies and in the production of tissue factor in coagulation process;
3. Evaluation of the effect of heparanase inhibitors on tissue factor expression and release.
All the compounds will be previously tested for selectivity, efficacy and safety.
Research in this field may contribute to clarify whether pharmacological regulation of heparanase might modify the disease activity, thus disclosing new potential therapeutic targets for APS.
The targets and compounds identified will create the basis for the development of novel types of drugs targeting cellular catabolism. Syntheses will be performed applying the most modern organic and pharmaceutical chemistry approaches to deliver compounds with maximized purity, yields and throughput. Techniques will include multicomponent reactions, liquid-phase parallel synthesis, microwave and flow chemistry techniques, under pressure and inert reactions, applying selective protective groups and stereoselective synthesis. Compounds will be produced in a sufficient quantity based on the needs of biological assays. The structure and purity (>95%) of the molecules will be confirmed by HPLC, LC-MS and NMR spectroscopy. In addition, taking advantage of the deeper knowledge of some pathogenic aspects of APS and on the recently discovered cell processes might represent an innovative tool for the discovery of new biomarkers, e.g. characteristics of germs, their enzymatic machinery, their interaction with host immune response and the induction of cellular response affecting survival. Expected results might rapidly have applicative implications aiming to evaluate their weight in diagnostic procedures and, even more, prognosis and response to treatment. Our final goal is to validate the identified biomarkers by larger clinical studies accordingly to specific therapeutic protocols based on the use of new strategies of care). All this could have great scientific value (for the progress of knowledge), great importance for clinical, preventive and therapeutic aspects (to better answer the patients needs), but also great economic relevance (to allow a rationalization of the health care costs). We expect that the achievements of the aims of this project will have positive consequences in terms of economic costs as well as for the life quality of patients suffering from APS.