Abstract 376: Traf-stop-hdl-nanoparticles Reduce Atherosclerosis
Inhibition of the co-stimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage results in immune suppression. Inhibition of the CD40-CD40L dyad further downstream in the signaling pathway is therefore required. The interaction between CD40 and its signaling intermediate TNF receptor associated factor 6 (TRAF6) plays a pivotal role in atherosclerosis. To identify drug like molecules that inhibit the CD40-TRAF6 interaction, an in silico structure-based virtual ligand screening approach was used. Several small molecule inhibitors (SMI) blocking CD40-TRAF6 interactions were identified. Surface plasmon resonance experiments confirmed direct binding of the compounds to the TRAF6 C-domain. Two of these SMIs, the TRAF-STOPs, reduced atherosclerosis by >40% in Apoe-/- mice, when they were treated from 12-18 wks of age, by hampering monocyte and neutrophil recruitment. In accordance, expression of chemokines and cytokines was remarkably reduced in compound treated macrophages.
Interestingly, when the TRAF-STOPs were administered to mice with existing atherosclerosis (from 22-30 wks of age), TRAF-STOPS were able to halt atherosclerosis, resulting in a >45% decrease in atherosclerotic plaque area.
However, these SMIs had a low solubility, and had a half-life of only 8 hrs, and had to be injected daily. To improve the therapeutic applicability of our TRAF-STOPs, TRAF-STOP 6877002 was packed in HDL-based nanoparticles, and administered twice a week for 6 wks (wk 12-18) to ApoE-/- mice. The HDL-TRAF-STOP nanoparticles preferentially homed to macrophages, and the expression level in plaque macrophages was high. HDL-TRAF-STOP nanoparticle treatment reduced atherosclerosis by 42.6%.
These newly developed, nanoparticle based CD40-TRAF6 inhibiting SMIs (TRAF-STOPs) are a promising lead for the development of therapeutics for the treatment of atherosclerosis.
Author Disclosures: T.T.P. Seijkens: None. B. Zarzycka: None. M.J. Gijbels: None. M.P.J. de Winther: None. C. Weber: None. G.A.F. Nicolaes: None. W.J. Mulder: None. E. Lutgens: None.
- © 2015 by American Heart Association, Inc.