Discovery of nitric oxide-inducing activities of synthetic LAM glycan motifs prepared by scalable rapid syntheses

Abstract

Enhancement of local nitric oxide (NO) concentration is important for the effectiveness of an adjuvant and for both innate and adaptive immunological responses. Currently, the information on the NO-inducing activities of lipoarabinomannan (LAM) glycan motifs on Mycobacterium tuberculosis (Mtb) is not possibly available. Thus, detailed studies on the structure-activity relationship of discrete LAM glycan motifs could provide valuable information towards the development of adjuvants and vaccines against Mtb. Using the newly-designed monomers and linker, the new rapid synthesis strategies demonstrated in this work enabled accessibilities to α(1→6)-D-mannans and α(1→5)-D-arabinans, which are the key LAM glycan motifs, with different controlled-sizes, in a scalable fashion. The glycans were evaluated for their ability to co-stimulate nitric oxide in macrophages. Only short and medium α(1→5)-D-arabinans show distinct abilities to strongly enhance LPS-induced nitric oxide, suggesting their potential use as stronger immunomodulators than α(1→6)-D-mannans, and thus, implying an unknown receptor responsible for this NO-inducing effect.