Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00532443" target="_blank" >RIV/61388963:_____/20:00532443 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1016/j.chembiol.2020.08.011" target="_blank" >https://doi.org/10.1016/j.chembiol.2020.08.011</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.chembiol.2020.08.011" target="_blank" >10.1016/j.chembiol.2020.08.011</a>

Result language
angličtina
Original language name
Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
<a href="/en/project/GA18-09556S" target="_blank" >GA18-09556S: Structural and biophysical basis of the reaction mechanism of intramembrane proteolysis</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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