jo7b03269_si_001.pdf (6.15 MB)
Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity
journal contribution
posted on 2018-05-21, 00:00 authored by Jessie
H. Bird, Ashna A. Khan, Naoya Nishimura, Sho Yamasaki, Mattie S. M. Timmer, Bridget L. StockerThe
macrophage inducible C-type lectin (Mincle) is a pattern recognition
receptor that recognizes trehalose dimycolate (TDM), and trehalose
dibehenate (TDB) and related trehalose diesters, and thus represents
a promising target for the development of vaccine adjuvants based
on the trehalose glycolipid scaffold. To this end, we report on the
synthesis of a series of long-chain α-branched, β-modified
trehalose monoesters and diesters to explore how glycolipid structure
affects signaling through Mincle. Key steps in our synthetic strategy
include a Fráter-Seebach α-alkylation to install the
C20 aliphatic lipid on a malic acid derivative, and the
formation of a β,γ-epoxide as an intermediate from which
modifications to the β-position of the lipid can be made. Biological
evaluation of the derivatives using nuclear factor of activated T
cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing
mMincle or hMincle revealed that the hMincle agonist activity of all
diesters was superior to that of the current lead trehalose glycolipid
adjuvant TDB, while the activity of several monoesters was similar
to that of their diester counterparts for mMincle, but all showed
reduced hMincle agonist activity. Taken together, diesters 2d–g are thus potent Mincle agonists and promising
vaccine adjuvants.