Clinical relevance of nitrated beta 2-glycoprotein I in antiphospholipid syndrome: Implications for thrombosis risk.

Β2-Glycoprotein I (ß2GPI) is an important anti-thrombotic protein and is the major auto-antigen in the antiphospholipid syndrome (APS). The clinical relevance of nitrosative stress in post translational modification of ß2GPI was examined.The effects of nitrated (n)ß2GPI on its anti-thrombotic properties and its plasma levels in primary and secondary APS were determined with appropriate clinical control groups. ß2-glycoprotein I was nitrated at tyrosines 218, 275 and 309. ß2-glycoprotein I binds to lipid peroxidation modified products through Domains IV and V. Nitrated ß2GPI loses this binding (p < 0.05) and had diminished activity in inhibiting platelet adhesion to vWF under high shear flow (p < 0.01). Levels of nß2GPI were increased in patients with primary APS compared to patients with either secondary APS (p < 0.05), autoimmune disease without APS (p < 0.05) or non-autoimmune patients with arterial thrombosis (p < 0.01) and healthy individuals (p < 0.05).In conclusion tyrosine nitration of plasma ß2GPI is demonstrated and has important implications with regards to the pathophysiology of platelet mediated thrombosis in APS. Elevated plasma levels of nß2GPI in primary APS may be a risk factor for thrombosis warranting further investigation.

In silico identification of new inhibitors for ßeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome.

Beta 2 glycoprotein I (ß2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). ß2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of ß2GPI binds to negatively charged phospholipids in the membrane via the fifth domain and causes blood clotting reactions. We applied a drug repurposing strategy using virtual screening and molecular dynamics to find the best FDA drugs against the fifth domain of ß2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of ß2GPI were selected by virtual screening. Among these drugs that had the most favorable ΔG, Vorapaxar and Antrafenine were selected for molecular dynamics (MD) simulation studies. MD simulation was performed to evaluate the stability of Vorapaxar and Antrafenine complexes and the effect of the two drugs on protein conformation. Also, MD simulation was done to investigate the effect of Antrafenine and Vorapaxar on the binding of ß2GPI to the platelet model membrane. According to the results, Vorapaxar and Antrafenine were bound to the protein with the favorable binding energy (Vorapaxar and Antrafenine binding energies are - 49.641 and - 38.803 kcal/mol, respectively). In this study, it was shown that unlike protein alone and protein in the Antrafenine complex, the protein in the Vorapaxar complex was completely separated from the model membrane after 350 ns. Moreover, Vorapaxar led to more changes in the activated J-shape of ß2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.