Rapid synthesis of α(1,2)-d-mannans on the surface of Mycobacterium tuberculosis and their nitric oxide-inducing activities

Abstract

The mannose cap motif, which consists of short-chain α(1,2)-d-mannans located on the non-reducing end of Mycobacterium tuberculosis’ mannose-capped lipoarabinomannan (ManLAM), exhibits strong binding affinities toward the lectins on mammalian host cells. The α(1,2)-d-mannans induce the immunosuppressive effects crucial for the survival and virulence of mycobacteria. However, the biological activities of discrete α(1,2)-d-mannans with different chain lengths remain unknown. In this study, the rapid synthesis of α(1,2)-d-mannans was rationally developed to increase the accessibility of α(1,2)-d-mannans. The rapid synthesis enabled simultaneous productions of the protected α(1,2)-d-mannans with chain lengths of 2–5 units, at room temperature (25 °C), within 4 h. After hydrolysis unmasking, different sizes of α(1,2)-d-mannans, and their α(1,6)-d-mannan counterparts were obtained and biologically evaluated. In summary, this work led to the optimally-designed low-steric-hindrance bicyclic orthoester monomer suitable for the gram-scale rapid synthesis of α(1,2)-d-mannans at 25 °C. This provided a basis for further development of more efficient syntheses for glycans with (1,2)-glycosidic linkages. Notably, the improved accessibility to these glycan motifs allowed us to discover that the α(1,2)-d-mannobioside could significantly enhance LPS-induced nitric oxide production in macrophages, suggesting its potential use as an immunomodulator and implying the existence of an unknown pathway or receptor responsible for this effect.