VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis

Abstract

SummaryAtherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…On the other hand, some commercial enterprises have explored the use of Lecinoxoids, which are ‘oxidized phospholipid-like small molecules,’ for anti-inflammatory therapies[153–155]. For instance, Lecinoxoid VB-201 had a notable effect in a mouse model of experimental autoimmune encephalomyelitis[155], and inhibited CD14 and TLR2-dependent inflammation[154]. Devising novel strategies for lowering OxPL levels as well as exploiting anti-inflammatory properties by developing small molecules modeled after OxPL should produce novel therapies against chronic inflammatory diseases.…”

The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

“…Furthermore, no clinical interventional studies targeting TLRs have been performed. However, in a study on murine and human monocytes, inhibition of TLR2 and CD14 (co-receptor of TLR4) by a small oxidized phospholipid leads to reduction of downstream inflammatory cytokines [182]. The same small molecule fed to rabbits reduced atherosclerosis [182].…”

“…However, in a study on murine and human monocytes, inhibition of TLR2 and CD14 (co-receptor of TLR4) by a small oxidized phospholipid leads to reduction of downstream inflammatory cytokines [182]. The same small molecule fed to rabbits reduced atherosclerosis [182]. Thus, it remains to be shown whether TLR-targeted strategies e either alone or combined with complement inhibitors -will prevent human atherosclerosis.…”

Identification of Motile Sperm Domain–Containing Protein 2 as Regulator of Human Monocyte Migration

“…Synthesis and biotin labeling of VB-201 was performed as described previously (13). VB-221 was synthesized and labeled in a similar manner, except for the starting compound of the latter (methanesulfonic acid-2-octyl-dodecyl ester).…”