GSK3036656 is an orally active inhibitor of M. tuberculosis leucyl-tRNA synthetase

Tuberculosis, one of the oldest known human diseases, is a potentially serious infectious disease that mainly affects the lungs. It is still one of the major causes of mortality since two million people die each year from this malady. Moreover, tuberculosis has many manifestations, affecting bone, the central nervous system, and many other organ systems. But it is primarily a pulmonary disease that is initiated by the deposition of Mycobacterium tuberculosis, contained in aerosol droplets, onto lung alveolar surfaces. The tiny droplets released into the air via coughs and sneezes can spread the bacteria that cause tuberculosis from person to person.

Mycobacterium tuberculosis (M. tuberculosis) is a species of pathogenic bacteria in the family Mycobacteriaceae. M. tuberculosis is the causative agent of tuberculosis. Meanwhile, it is a small bacillus that can withstand weak disinfectants and survive in a dry state for weeks. Compared to other commonly studied bacteria, M. tuberculosis has a remarkably slow growth rate, divides every 18-24 hours. M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. In a classic experiment, purified culture of virulent M. tuberculosis can induce tuberculosis in rabbits.

GSK3036656 (GSK070) is a potent leucyl-tRNA synthetase (LeuRS) inhibitor.

GSK30366 is a potent selective and orally active LeuRS inhibitor, with high specificity and selectivity over the human mitochondrial and cytoplasmic LeuRS enzyme. GSK3036656 suppresses protein synthesis in M. tuberculosis by selectively inhibiting the LeuRS enzyme. In vitro, GSK3036656 exhibits good anti-tuberculosis activity. In addition, it shows remarkable pharmacokinetic profiles and efficacy against M. tuberculosis in mouse tuberculosis infection models. And it demonstrates superior tolerability over initial leads. Currently, GSK3036656 has been progressed to clinical development for the research of tuberculosis.

All in all, GSK3036656 is a potent, selective, and orally active inhibitor of M. tuberculosis LeuRS.


Smith I, et, al. Clin Microbiol Rev. 2003 Jul;16(3):463-96.