Identification and Validation of Compounds Targeting Leishmania major Leucyl-Aminopeptidase M17
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60076658%3A12310%2F24%3A43908381" target="_blank" >RIV/60076658:12310/24:43908381 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00009" target="_blank" >https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00009</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acsinfecdis.4c00009" target="_blank" >10.1021/acsinfecdis.4c00009</a>
Alternative languages
Result language
angličtina
Original language name
Identification and Validation of Compounds Targeting Leishmania major Leucyl-Aminopeptidase M17
Original language description
Leishmaniasis is a neglected tropical disease; there is currently no vaccine and treatment is reliant upon a handful of drugs suffering from multiple issues including toxicity and resistance. There is a critical need for development of new fit-for-purpose therapeutics, with reduced toxicity and targeting new mechanisms to overcome resistance. One enzyme meriting investigation as a potential drug target in Leishmania is M17 leucyl-aminopeptidase (LAP). Here, we aimed to chemically validate LAP as a drug target in L. major through identification of potent and selective inhibitors. Using RapidFire mass spectrometry, the compounds DDD00057570 and DDD00097924 were identified as selective inhibitors of recombinant Leishmania major LAP activity. Both compounds inhibited in vitro growth of L. major and L. donovani intracellular amastigotes, and overexpression of LmLAP in L. major led to reduced susceptibility to DDD00057570 and DDD00097924, suggesting that these compounds specifically target LmLAP. Thermal proteome profiling revealed that these inhibitors thermally stabilized two M17 LAPs, indicating that these compounds selectively bind to enzymes of this class. Additionally, the selectivity of the inhibitors to act on LmLAP and not against the human ortholog was demonstrated, despite the high sequence similarities LAPs of this family share. Collectively, these data confirm LmLAP as a promising therapeutic target for Leishmania spp. that can be selectively inhibited by drug-like small molecules.
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
10601 - Cell biology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ACS Infectious Diseases
ISSN
2373-8227
e-ISSN
2373-8227
Volume of the periodical
10
Issue of the periodical within the volume
6
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
2002-2017
UT code for WoS article
001226092200001
EID of the result in the Scopus database
2-s2.0-85193566602