Inhibitors of Rickettsia prowazekii methionine aminopeptidase 1 identified from the Pandemic Response Box

Methionine aminopeptidase (MetAp) enzymes catalyze the post-translational removal of the initiator methionine residue in newly synthesized proteins, a process that is often essential in the maturation of proteins. Consequently, these enzymes serve as important targets for drug development. Rickettsia prowazekii (Rp) is an obligate coccobacillus and the causative agent of the louse-borne epidemic typhus and despite adequate treatment causes a latent infection. This research aimed to identify potential anti-rickettsial agents by screening 400 compounds from the MMV Pandemic Response Box against RpMetAp1. Overall, 19 compounds were identified that possessed IC₅₀ values from 10 µM to 340 nM. The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC₅₀ of 340 nM. The selected hits serve as chemical leads that can be used for the development of potent inhibitors of the RpMetAp1 enzyme.