Evaluating Antimalarial Proteasome Inhibitors for Efficacy in Babesia Blood Stage Cultures

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F24%3A00601793" target="_blank" >RIV/60077344:_____/24:00601793 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388963:_____/24:00601793 RIV/60076658:12310/24:43908696

Výsledek na webu

<a href="https://doi.org/10.1021/acsomega.4c04564" target="_blank" >https://doi.org/10.1021/acsomega.4c04564</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsomega.4c04564" target="_blank" >10.1021/acsomega.4c04564</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Evaluating Antimalarial Proteasome Inhibitors for Efficacy in Babesia Blood Stage Cultures

Popis výsledku v původním jazyce

Tick-transmitted Babesia are a major global veterinary threat and an emerging risk to humans. Unlike their Plasmodium relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the Babesia proteasome holds promise for drug development. In this study, we screened a library of peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B for their activity against Babesia. Several of these compounds showed activity against both the asexual and sexual blood stages of Plasmodium falciparum. These compounds inactivate beta 5 proteasome subunit activity in the lysates of Babesia divergens and Babesia microti in the low nanomolar range. Several compounds were tested with the purified B. divergens proteasome and showed IC50 values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited B. divergens growth in bovine erythrocyte cultures with solid EC50 values, but importantly, they appeared less toxic to human cells than carfilzomib. These compounds therefore offer a wider therapeutic window and provide new insights into the development of small proteasome inhibitors as selective drugs for babesiosis.

Název v anglickém jazyce

Evaluating Antimalarial Proteasome Inhibitors for Efficacy in Babesia Blood Stage Cultures

Popis výsledku anglicky

Tick-transmitted Babesia are a major global veterinary threat and an emerging risk to humans. Unlike their Plasmodium relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the Babesia proteasome holds promise for drug development. In this study, we screened a library of peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B for their activity against Babesia. Several of these compounds showed activity against both the asexual and sexual blood stages of Plasmodium falciparum. These compounds inactivate beta 5 proteasome subunit activity in the lysates of Babesia divergens and Babesia microti in the low nanomolar range. Several compounds were tested with the purified B. divergens proteasome and showed IC50 values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited B. divergens growth in bovine erythrocyte cultures with solid EC50 values, but importantly, they appeared less toxic to human cells than carfilzomib. These compounds therefore offer a wider therapeutic window and provide new insights into the development of small proteasome inhibitors as selective drugs for babesiosis.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

ACS Omega

ISSN

2470-1343

e-ISSN

2470-1343

Svazek periodika

9

Číslo periodika v rámci svazku

45

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

44989-44999

Kód UT WoS článku

001344916100001

EID výsledku v databázi Scopus

2-s2.0-85207418461