Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis

Kendal T. Ryter, George Ettenger, Omer K. Rasheed, Cassandra Buhl, Robert Child, Shannon M. Miller, David Holley, Alyson J. Smith, Jay T. Evans

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalJournal of Medicinal Chemistry
Volume63
Issue number1
DOIs
StatePublished - Jan 9 2020

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