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Cited by 35Malaria Research and ControlProtease and Inhibitor MechanismsEnzyme Structure and Function

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Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Open access
Hodder, Anthony N., Christensen, Janni, Scally, Stephen, Triglia, Tony, Ngo, Anna, Birkinshaw, Richard W., Bailey, Brodie, Favuzza, Paola, Dietrich, Melanie H., Tham, Wai-Hong, Czabotar, Peter E., Lowes, Kym, Guo, Zhuyan, Murgolo, Nicholas, Lera Ruiz, Manuel de, McCauley, John A., Sleebs, Brad E., Olsen, David, Cowman, Alan F.·2022·Structure
DOI 10.1016/j.str.2022.03.018

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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.

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Metadata

Authors
Hodder, A. N., Christensen, J., Scally, S., Triglia, T., Ngo, A., Birkinshaw, R. W., Bailey, B., Favuzza, P., Dietrich, M. H., Tham, W.-H., Czabotar, P. E., Lowes, K., Guo, Z., Murgolo, N., Lera Ruiz, M. D., McCauley, J. A., Sleebs, B. E., Olsen, D., & Cowman, A. F.
Affiliations
  • The University of Melbourne (AU)
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Cowman, Alan F.
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
2022-07
Volume
30
Issue
7
Pages
947-961.e6
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/j.str.2022.03.018
OpenAlex
W4226110122
Cited by
35
References
1
Citations by year
2026: 10 · 2025: 10 · 2024: 6 · 2023: 3 · 2022: 6
FWCI
5.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • ANU Open Research (Australian National University) (submittedVersion)
Funders
  • Australian Nuclear Science and Technology Organisation
  • Wellcome Trust (109662, 202749, /Z/15/Z, 202749/Z/16/Z, 109662/Z/15/Z)
  • Australian Government
  • Commonwealth Scientific and Industrial Research Organisation
  • Australian Cancer Research Foundation
  • Australian Synchrotron
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
Plasmodium falciparum, Plasmodium vivax, aspartyl protease inhibitors, drug selectivity, substrate specificity, S region, enzyme kinetics, protein-ligand binding, antimalarial drug candidates
MeSH terms
Kinetics, Plasmodium falciparum, Substrate Specificity, Protozoan Proteins, Aspartic Acid Endopeptidases

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