Inhibition of beta 2glycoprotein I binding to anionic phospholipids: a strategy for the development of antiphospholipid syndrome-specific drugs.
The binding of beta 2glycoprotein I (beta 2GPI) to anionic phospholipids (PL) leads to the presentation of one or more epitopes recognized by autoantibodies from patients with antiphospholipid syndrome (APS). The inhibition of beta 2GPI binding to PL mixtures coated on polystyrene microtiter wells (MTW) and to large, multilamellar PL vesicles (LMV) was examined. Inhibitors included phosphorylated monosaccharide metabolites, myo-inositol monophosphate (IMP), hexaphosphate (IHP) and hexasulfate (IHS), pyrophosphate (PPi), methyl bisphosphonate (MBP) and phenyl phosphonate, and a series of carboxylic and aromatic sulfonic acids. Inhibitors were incubated with beta 2GPI at 37 degrees C for 2 hr either with dimyristoylphosphatidic acid, 80%/dimyristoylphosphatidyl choline, 20% (DMPA/DMPC) coated on MTW or in a suspension of LMV. Phospholipid-bound beta 2GPI to PA/PC on MTW was detected using an immunoassay based on rabbit anti-beta 2GPI; free beta 2GPI (not bound to LMV) was detected by fluorescence spectroscopy. Inhibition was studied over the range 0.01-9.0 mumoles/10(-4)L (0.1-90 mM). Inhibition at maximum concentration in the MTW system ranged from 0.1% (for ADP) to > 94% (for IHP). IHP also provided the greatest inhibition in the LMV system (76%) and was also effective in displacing beta 2GPI already bound to PL surfaces (approximately 50% displaced at 0.25 mM). These data suggest that a strategy for development of therapeutic agents for APS may be based on the use of small cyclic, organic oligoanions such as inositol derivatives to act as ligands for lysine residues at the PL binding site of beta 2GPI.
Kohles
J D
JD
Department of Medicine, St. Joseph's Hospital and Medical Center, Paterson, NJ 07503, USA.
Petersheim
M
M
DeBari
V A
VA
D000818:Animals; D000838:Anions; D016736:Antiphospholipid Syndrome / Q000188:drug therapy*; D001323:Autoantibodies / Q000276:immunology; D015195:Drug Design; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D010743:Phospholipids / Q000378:metabolism*; D011817:Rabbits
D000838:Anions; D001323:Autoantibodies; D006023:Glycoproteins; D010743:Phospholipids