Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Chemistry - A European Journal

ISSN

0947-6539

e-ISSN

1521-3765

Svazek periodika

29

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

8

Strana od-do

e202203958

Kód UT WoS článku

000943866600001

EID výsledku v databázi Scopus

2-s2.0-85149300061