In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.35.suppl_1.376
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1494427-3
