Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax
- Author(s)
- Hodder, AN; Christensen, J; Scally, S; Triglia, T; Ngo, A; Birkinshaw, RW; Bailey, B; Favuzza, P; Dietrich, MH; Tham, WH; Czabotar, PE; Lowes, K; Guo, Z; Murgolo, N; Lera Ruiz, M; McCauley, JA; Sleebs, BE; Olsen, D; Cowman, AF;
- Journal Title
- Structure
- Publication Type
- epub ahead of print
- Abstract
- Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.
- Keywords
- antimalarial; aspartic protease; enzzyme kinetics; malaria; plasmepsin IX; plasmepsin X; protein-drug structure
- Research Division(s)
- Advanced Technology And Biology; Chemical Biology; Structural Biology; Infectious Diseases And Immune Defence
- PubMed ID
- 35460613
- Publisher's Version
- https://doi.org/10.1016/j.str.2022.03.018
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-05-03 09:18:32
Last Modified: 2022-05-03 09:28:46