The Synthesis of Modified Trehalose Glycolipids: Towards Understanding Mincle and MCL Binding

Abstract

Trehalose glycolipids are a diverse family of long-chain fatty acid diesters isolated from the cell walls of bacteria, in particular Mycobacterium species including M. tuberculosis. These molecules possess an array of biological activities which contribute to the survival and virulence of the organism,however, it is their activity as potent stimulators of innate and early adaptive immunity for which they are of interest. In particular, trehalose glycolipids have an application as adjuvants in vaccines and immunotherapies, for diseases such as tuberculosis (TB) and cancer. Recently, the macrophage-inducible C-type lectin, Mincle, and the macrophage C-type lectin, MCL, were identified as receptors for trehalose glycolipids, however, the exact mechanisms by which these receptors recognise and bind glycolipids is, as yet, unknown.This thesis presents the synthesis of a variety of structurally diverse trehalose glycolipid analogues. As such, three mycolic acids bearing a C22 α-chain and diversified meromycolate branches were prepared from an epoxide intermediate, itself prepared in eight steps from commercially available starting materials. The mycolic acids were then coupled to TMS-trehalose and subsequently deprotected to give the mono-and diester derivatives, 1a-cand 2c, which will be assessed for their immunostimulatory activity through the activation of wild type and Mincle-/-murine macrophages. This work provides a first step towards determining how the structures of trehalose glycolipids influence Mincle and MCL binding and activity, and allow for the development of improved trehalose glycolipids for use in adjuvant therapies.