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 IC ₅₀ values from 10 µM to 340 nM. The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC ₅₀ of 340 nM. The selected hits serve as chemical leads that can be used for the development of potent inhibitors of the RpMetAp1 enzyme.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Timothy Hagen reports equipment, drugs, or supplies was provided by Medicines for Malaria Venture. Timothy Hagen reports equipment, drugs, or supplies was provided by Seattle Structural Genomics Center for Infectious Disease. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Ltd.)