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Characterization of P. falciparum dipeptidyl aminopeptidase 3 specificity identifies differences in amino acid preferences between peptide-based substrates and covalent inhibitors

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00510417" target="_blank" >RIV/61388963:_____/19:00510417 - isvavai.cz</a>

  • Result on the web

    <a href="https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.14953" target="_blank" >https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.14953</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1111/febs.14953" target="_blank" >10.1111/febs.14953</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Characterization of P. falciparum dipeptidyl aminopeptidase 3 specificity identifies differences in amino acid preferences between peptide-based substrates and covalent inhibitors

  • Original language description

    Malarial dipeptidyl aminopeptidases (DPAPs) are cysteine proteases important for parasite development thus making them attractive drug targets. In order to develop inhibitors specific to the parasite enzymes, it is necessary to map the determinants of substrate specificity of the parasite enzymes and its mammalian homologue cathepsin C (CatC). Here, we screened peptide-based libraries of substrates and covalent inhibitors to characterize the differences in specificity between parasite DPAPs and CatC, and used this information to develop highly selective DPAP1 and DPAP3 inhibitors. Interestingly, while the primary amino acid specificity of a protease is often used to develop potent inhibitors, we show that equally potent and highly specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates. Finally, our homology modelling and docking studies provide potential structural explanations of the differences in specificity between DPAP1, DPAP3, and CatC, and between substrates and inhibitors in the case of DPAP3. Overall, this study illustrates that focusing the development of protease inhibitors solely on substrate specificity might overlook important structural features that can be exploited to develop highly potent and selective compounds.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10608 - Biochemistry and molecular biology

Result continuities

  • Project

    <a href="/en/project/EF16_019%2F0000729" target="_blank" >EF16_019/0000729: Chemical biology for drugging undruggable targets</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2019

  • Confidentiality

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

Data specific for result type

  • Name of the periodical

    FEBS Journal

  • ISSN

    1742-464X

  • e-ISSN

  • Volume of the periodical

    286

  • Issue of the periodical within the volume

    20

  • Country of publishing house

    GB - UNITED KINGDOM

  • Number of pages

    26

  • Pages from-to

    3998-4023

  • UT code for WoS article

    000491083000006

  • EID of the result in the Scopus database

    2-s2.0-85068093859