AI Article Synopsis
- PMIX and PMX are important proteases in Plasmodium spp. that facilitate essential processes like egress and invasion in their lifecycle.
- WM4 and WM382 are inhibitors of these proteases, with WM4 specifically targeting PMX and WM382 acting on both PMIX and PMX.
- Research into the binding interactions and substrate specificity of these inhibitors helps clarify their mechanism, providing insights that could aid in developing new treatments.
Article 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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| http://dx.doi.org/10.1016/j.str.2022.03.018 | DOI Listing |
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Article Synopsis
- PMIX and PMX are important proteases in Plasmodium spp. that facilitate essential processes like egress and invasion in their lifecycle.
- WM4 and WM382 are inhibitors of these proteases, with WM4 specifically targeting PMX and WM382 acting on both PMIX and PMX.
- Research into the binding interactions and substrate specificity of these inhibitors helps clarify their mechanism, providing insights that could aid in developing new treatments.
Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle.
Cell Host Microbe
April 2020
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address:
Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets.
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