Pharmaceutica Analytica Acta

Structure-based discovery of TRAF-stops: Small molecule inhibitors of the CD40-TRAF6 interaction to block inflammatory pathways in atherosclerosis and other immune-modulated pathologies

17^th Annual Congress on Pharmaceutics & Drug Delivery Systems

September 20-22, 2018 Prague, Czech Republic

Gerry Nicolaes

Maastricht University, Netherlands

Scientific Tracks Abstracts: Pharm Anal Acta

Abstract:

Chronic inflammation of the arterial wall, as occurs in atherosclerosis, may lead to stroke or myocardial infarction. One of the interactions that are known to drive this inflammatory reaction in atherosclerosis is that between CD40 protein and its ligand CD40L. For CD40 to elicit intracellular signaling, it needs to recruit adaptor proteins called tumor necrosis factor receptor-associated factors (TRAFs). Interactions of CD40 with TRAF6 but not those with TRAF2/3/5 are critically involved in atherosclerosis progression and plaque stabilization; which makes the CD40-TRAF6 interaction a downstream target for potential inhibition of inflammatory processes in atherosclerosis. We have used a hierarchical protocol of structure-based virtual ligand screening (SBVLS) to discover small drug-like inhibitors of the CD40-TRAF6 interaction and combined in silico researches with in vitro cell-based assays and biophysical methods. Top hit molecules were administered to Apoe-/- mice models of initial and of established atherosclerosis. In both models hit molecules, named TRAF-stops reduced total plaque area and changed the plaque phenotype to a more stable phenotype. Intravital microscopy showed a reduction in leukocyte recruitment. We furthermore used rHDL nanoparticles loaded with one of the compounds to specifically target TRAF-stops to macrophages, resulting in clear attenuation of atherosclerosis. The compounds inhibited CD40-TRAF6 interaction by direct binding to TRAF6 C-domain and reduced progression of atherosclerosis by inhibition of chemokine-mediated leukocyte influx into the arterial wall, while the molecules did not impair classical immune pathways of CD40. Our results indicate possibilities of longterm therapeutic inhibition of CD40-TRAF6 interactions in atherosclerosis and possibly other inflammatory diseases.

Biography :

Gerry Nicolaes has completed his PhD from the Maastricht University and Post-doctoral studies from Lund University (Sweden). He is a Unit Leader in the Department of Biochemistry at the Cardiovascular Research Institute Maastricht, has an appointment at the Academic Medical Centre Amsterdam and is CSO for Matisse Pharmaceuticals BV, a start-up university spin-off. He has published more than 80 peer-reviewed papers in the fields of coagulation, atherosclerosis, inflammation and drug design.

E-mail: g.nicolaes@maastrichtuniversity.nl