Characterization of OJT007 and OJT008 as Inhibitors of Methionine Aminopeptidases from Mycobacterium tuberculosis

Abstract

Despite recent advances in the diagnosis of Tuberculosis (TB), the therapeutic management of this ancient disease is still challenging. Mycobacterium tuberculosis, the causative infectious agent of TB, is the number one cause of death from infectious diseases in the world. According to World Health Organization TB report, globally, 558, 000 people developed multi‐drug resistance TB that was resistant to the most efficacious first‐line drug, rifampicin. The emergence of multi‐drug and extensively drug resistance strains of M. tuberculosis has made the requirement for the development of novel anti‐TB agents imperative. Our research focuses on targeting Methionine Aminopeptidase (MetAP) an essential protein for growth of M. tuberculosis. MetAP is a dinuclear metalloprotease that catalyzes the process of removal of N‐terminal methionine during protein synthesis. N‐terminal methionine excision from peptides and proteins, is a universally conserved process required for stability, localization, biologic maturation and post‐translational modifications of some proteins. This essential role of MetAPs makes this enzyme an attractive target for the development of new therapeutic agents for treatment of TB. Our hypothesis is that, the development of potent and selective mycobacterial MetAP inhibitors may serve as therapeutic agents against infections caused by M. tuberculosis. Here, we report the characterization and pre‐clinical development of two novel structurally diverse small molecules (OJT007 and OJT008), as inhibitors of M. tuberculosis MetAP with potent activity against M. tuberculosis in the low micromolar range in vitro. These results suggest that OJT007 and OJT008 are potential lead compounds for the development of novel small molecules for the therapeutic management of TB. This target‐based approach has demonstrated the utility of MetAPs as promising antimycobacterial targets. Furthermore, we have developed optimal co‐solvent formulations for both OJT007 and OJT008. Preliminary in vivo pharmacokinetic studies for both compounds are in progress. The discovery of new lead compounds to the diminishing anti‐TB pipeline could have potential impact in accelerating the development of new drug candidates for treatment of drug‐sensitive and drug‐resistant TB. In addition, OJT007 and OJT008 may serve as novel chemical probes for understanding the essential role of N‐terminal methionine excision in TB biology.Support or Funding InformationThis research was supported in part, by research infrastructure support from RCMI grant number 2G12MD007605‐22A1 from the NIMHD/NIH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.