| Literature DB >> 35460613 |
Anthony N Hodder1, Janni Christensen1, Stephen Scally1, Tony Triglia2, Anna Ngo2, Richard W Birkinshaw1, Brodie Bailey1, Paola Favuzza1, Melanie H Dietrich1, Wai-Hong Tham1, Peter E Czabotar1, Kym Lowes2, Zhuyan Guo3, Nicholas Murgolo3, Manuel de Lera Ruiz3, John A McCauley3, Brad E Sleebs1, David Olsen3, Alan F Cowman4.
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.Entities:
Keywords: antimalarial; aspartic protease; enzzyme kinetics; malaria; plasmepsin IX; plasmepsin X; protein-drug structure
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Year: 2022 PMID： 35460613 DOI： 10.1016/j.str.2022.03.018
Source DB: PubMed Journal: Structure ISSN： 0969-2126 Impact factor: 5.871