ArticleCell chemical biology2020
Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria.
Article in Cell chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Targeting the Membrane-Embedded Rhomboid Protease GlpG: A Multimodal Strategy for Inhibitor Discovery and Mechanistic Insight.Angewandte Chemie (International ed. in English) · 2026Article
- Rhomboid protease Rhbdl2 regulates macrophage recruitment and wound regeneration in zebrafish.bioRxiv : the preprint server for biology · 2026Article
- Optimization and Characterization of the Antimalarial Activity ofJournal of medicinal chemistry · 2025Article
- Trends on Potential Boron-containing Drugs by Advancements in Ligand-protein Crystals Complexes.Current medicinal chemistry · 2025Review
- The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery.The Journal of biological chemistry · 2025Article
- 4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL.ACS medicinal chemistry letters · 2024Article
- AnbioRxiv : the preprint server for biology · 2024Article
- Comparative Degradome Analysis of the Bovine Piroplasmid PathogensPathogens (Basel, Switzerland) · 2023Article
- Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.Journal of medicinal chemistry · 2023Article
- Targeting theHeliyon · 2022Review
- Unraveling the Complexity of the Rhomboid Serine Protease 4 Family ofPathogens (Basel, Switzerland) · 2022Article
- Novel inhibitors and activity-based probes targeting serine proteases.Frontiers in chemistry · 2022Article
- In Silico Survey and Characterization ofPathogens (Basel, Switzerland) · 2021Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.
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Registered trials
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