Synthesis and biological activity of Ub‐2 derived peptides as potential host directed anti‐tubercular therapy

We have reported a methodology for the modulation of N‐terminal of the Ub2 peptide using azaGly as a linker with differently substituted heteroaryl moieties along with the replacement of C‐terminal glycine with azaGly. The study suggests that the formed Ub2 peptides can effectively eliminate the mycobacteria from the infected macrophage possibly by the mechanism of lysosomal acidification and enhancement of phagolysosome formation involving host directed therapy

Abstract

The correlation of mycobactericidal property of macrophages with its potential to deliver bacteria to hydrolytic lysosomes, augmented with Ubiquitin derived peptides (Ub2) activates the process of autophagy. This leads to the formation of phagolysosomes supported by factor involving increased cationic charges which regulates the acidic pH causing elimination of Mycobacterium. To better understand this interaction of cationic rich ubiquitin‐derived peptides with mycobacteria and to identify putative mycobacterial intrinsic resistance mechanisms for phagolysosome formation, we have synthesized a new series of Ub2 peptides, wherein the Gly residues are replaced with azaGly with the aim to improve metabolic stability. In addition to that a new methodology is reported for the synthesis of heteroaryltethered peptides using azaGly as a linker. We have demonstrated that positive puncta (directly proportional to the acidification of lysosome) in cytosol was significantly increased after 6‐hours on the treatment of macrophage with Ub2 peptide derivatives (1, 6, 10 and 11) causing the higher intensity of lysosome observed through Lysotracker red dye. The CD Spectral studies are carried out in water and water:TFE mixture and demonstrated that the Ub2 peptides having helix forming tendency in presence of TFE. The recognizable intracellular killing of Mycobacterium tuberculosis by Ub2 peptides provides a new approach for host directed therapy.

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