Methionine aminopeptidases (MetAPs) are ubiquitous enzymes that are essential for the survival of various bacteria. The enzyme removes the N-terminal methionine from nascent proteins to initiate post-secondary modification. The ultimate goal for this study is to identify selective inhibitors targeting methionine aminopeptidases (MetAPs) of infective organisms, including Burkholderia pseudomallei, Plasmodium falciparum, and Rickettsia prowazekii, to generate novel anti-infective agents. Our studies displayed the ability of nitroxoline inhibitors of both Burkholderia pseudomallei methionine aminopeptidase 1 (BpMetAP1) and Plasmodium falciparum methionine aminopeptidase 2 (PfMetAP2) to inhibit cell growth of the target organisms. In addition, in vitro compound screening of 400 compounds with antimalarial activities from Medicines for Malaria identified 19 lead compounds with IC50 of less than 10 µM against PfMetAP2. Finally, initial studies to discover novel anti-rickettsial therapeutics through the synthesis and design of inhibitors targeting Rickettsia prowazekii methionine aminopeptidase (RpMetAP) will be discussed. In our preliminary study, five different chemical classes of compounds were screened against RpMetAP in a fluorescent plate-based assay. Notably, furan carboxylic acid and oxine derivatives were observed to exhibit inhibition potencies (IC50 values) less than 1 µM. Design and synthesis of analogs from these active series may lead to potential treatments for Rickettsia prowazekii.

Methionine aminopeptidases (MetAPs) as promising targets toward discovery of novel anti-infective agents

249th National Meeting (2015)

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