Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) continues to be a major health threat worldwide, and the development of Mtb vaccines could play a pivotal role in the prevention and control of this devastating epidemic. Th17-mediated immunity has been implicated in disease protection correlates of immune protection against Mtb. Currently, there are no approved adjuvants capable of driving a Th17 response in a vaccine setting. Recent clinical trial results using trehalose dibehenate have demonstrated a formulation-dependant proof of concept adjuvant system CAF01 capable of inducing long-lived protection. We have discovered a new class of Th17-inducing vaccine adjuvants based on the natural product Brartemicin. We synthesized and evaluated the capacity of a library of aryl trehalose derivatives to drive immunostimulatory reresponses and evaluated the structure–activity relationships in terms of the ability to engage the Mincle receptor and induce production of innate cytokines from human and murine cells. We elaborated on the structure–activity relationship of the new scaffold and demonstrated the ability of the lead entity to induce a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells and demonstrated efficacy in generating antibodies in combination with tuberculosis antigen M72 in a mouse model.

Design of Trehalose‐Based Amide/Sulfonamide C‐type Lectin Receptor Signaling Compounds

“…As our continued interest in exploring the potential utility of 6,6'-aryl α,α-d-trehalose analogues on Mincle-binding and cytokine signaling as vaccine adjuvants have generated several novel compounds with improved potency and solubility over the currently available Mincle ligands such as TDB and TDM. [13,14,17,18] The natural extension of structure-activity studies is the synthesis of 6,6'-aryl amide α,α-d-trehalose and 6,6'-aryl sulfonamide α,α-d-trehalose analogues related to previously prepared ester analogues [17b] to investigate the impact of the aryl-trehalose linkage on Mincle selective cytokine signaling. 6,6'-diamino trehalose (3) is a key intermediate for the synthesis of the targeted trehalose diamides (TDA's) was obtained as shown in Table 1.…”

Emerging glyco‐based strategies to steer immune responses

“…These include among others, the S‐layer glycoprotein from Lactobacillus kefiri [ 114 ], whose adjuvant activity was dependent on the glycan components and on the presence of Mincle and CARD9 in mouse DCs. Brartemicin, a glycosyl glycoside derivative isolated from Nonomuraea species with similarity in structure to TDB, was originally identified for its antitumor activities and is also recognized by Mincle [ 109 , 115 ]. Lipidated Brartemicin analogues and especially the o ‐substituted variant showed strong inflammatory activities, inducing Mincle signaling and pro‐inflammatory cytokine responses in both mouse bone marrow‐derived macrophages and human monocytes [ 116 , 117 ].…”

Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN

“…In cellular assays, however, brartemicin itself evoked no or a less effective Mincle-induced immune activation in peripheral blood mononuclear cells (PBMCs) or bone marrow-derived macrophages (BMDM). 74,75 Synthetic brartemicin analogues containing aliphatic aryl ethers showed a much improved binding affinity in a direct ELISA-type binding assay. 74 An intermediate chain length (C7, 8) was found to give a more potent interaction than longer variants (C18, 9).…”