Targeted Degradation of Mycobacterial PknG for Host Control of Tuberculosis

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

ABSTRACT Mycobacterium tuberculosis (Mtb) is one of the world’s leading causes of death from infection. Curative chemotherapeutic regimens exist, but they are long, often toxic and plagued by emergence of drug resistance. Macrophages are the major cellular locale for Mtb in the host before formation of largely acellular cavities. Adjunctive therapies could potentially speed the cure of tuberculosis by improving the ability of macrophages to kill Mtb. Within macrophages, Mtb secretes an enzyme, protein kinase G (PknG), that enters the macrophage cytosol, where it blocks fusion of lysosomes with phagosomes and promotes degradation of proteins that help activate macrophage mycobactericidal mechanisms. Targeted protein degradation (TPD) is a promising new therapeutic avenue. Compounds that mediate TPD differ from active site inhibitors by working catalytically and therefore sub-stoichiometrically with respect to the target. TPD as a form of anti-mycobacterial chemotherapy has been introduced for model targets in non-tuberculous mycobacteria, but not yet demonstrated for an Mtb protein in its native state. Here we propose to exploit the macrophage’s ubiquitin-proteasome system to degrade PknG as it has been secreted by Mtb and has entered the macrophage cytosol by synthesizing and testing proteolysis-targeting chimeras (PROTACs) that link a PknG inhibitor to binders of the E3 ubiquitin ligases cereblon and von-Hippel Lindau.