The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

Abstract

Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC values of less than 10 µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

Rickettsia Aglow: A Fluorescence Assay and Machine Learning Model to Identify Inhibitors of Intracellular Infection

“…19 In contrast, we note a target-based screen versus R. prowazekii methionine aminopeptidase. 50 Our empirical screen of 2000 compounds afforded 113 compounds with a promising profile: ≥50% reduction in RFU compared to controls with <25% Vero cell viability reduction. From these efforts, duartin emerged as the most promising compound.…”

Discovery of Potential Antituberculosis Agents Targeted Methionine Aminopeptidase 1 of Mycobacterium tuberculosis by the Developed Fluorescent Probe

“…13−15 Methionine aminopeptidase 1 of Mycobacterium tuberculosis (MtMET-AP1) has found the key factor of virulence in host cells of M. tuberculosis, by providing the initial methionine for protein expression, and strongly affected the pathogenic abilities of M. tuberculosis, which is thought to be a new type of drug targets against M. tuberculosis. 13,16 Thus, the establishment of a method for detecting the endogenous activity of MtMET-AP1 in M. tuberculosis and high-throughput screening of inhibitors are new means of drug development and are essential for the development of therapeutic approaches for TB.…”

“…Methionine aminopeptidase 1 (MET-AP1, EC 3.4.11.18), known as a ubiquitous binuclear metalloproteinase, especially hydrolyzes the methionine residues from the N -terminal of proteins or peptides. , Its encoding gene is essential for cell survival from bacteria to humans in all forms of life. − Methionine aminopeptidase 1 of Mycobacterium tuberculosis (MtMET-AP1) has found the key factor of virulence in host cells of M. tuberculosis, by providing the initial methionine for protein expression, and strongly affected the pathogenic abilities of M.…”

“…tuberculosis, which is thought to be a new type of drug targets against M. tuberculosi s . , Thus, the establishment of a method for detecting the endogenous activity of MtMET-AP1 in M. tuberculosis and high-throughput screening of inhibitors are new means of drug development and are essential for the development of therapeutic approaches for TB.…”

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction

“…The antipathogenic effect is one of the most studied areas, including different mechanisms of action: increasing cell membrane permeability [32], inhibition of MetAP1 [33,34], ubiquinone synthesis [35], or type III secretion [36,37]. Antifungal activity of these 8HQs has been assessed among humans [34,38,39] and phyto-pathogens [40,41]. Furthermore, a potential antiprion compound has also been identified [42].…”