Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00570610" target="_blank" >RIV/61388963:_____/23:00570610 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1002/chem.202203958" target="_blank" >https://doi.org/10.1002/chem.202203958</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/chem.202203958" target="_blank" >10.1002/chem.202203958</a>
Alternative languages
Result language
angličtina
Original language name
Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors
Original language description
Here, we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.
Czech name
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Czech description
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Classification
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
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Chemistry - A European Journal
ISSN
0947-6539
e-ISSN
1521-3765
Volume of the periodical
29
Issue of the periodical within the volume
20
Country of publishing house
DE - GERMANY
Number of pages
8
Pages from-to
e202203958
UT code for WoS article
000943866600001
EID of the result in the Scopus database
2-s2.0-85149300061