Cargando…

The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site

BACKGROUND: Malaria kills over 400,000 people each year and nearly half the world’s population live in at-risk areas. Progress against malaria has recently stalled, highlighting the need for developing novel therapeutics. The parasite haemoglobin degradation pathway, active in the blood stage of the...

Descripción completa

Detalles Bibliográficos
Autores principales: Machin, Jonathan M., Kantsadi, Anastassia L., Vakonakis, Ioannis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889325/
https://www.ncbi.nlm.nih.gov/pubmed/31791339
http://dx.doi.org/10.1186/s12936-019-3043-0
_version_ 1783475391996887040
author Machin, Jonathan M.
Kantsadi, Anastassia L.
Vakonakis, Ioannis
author_facet Machin, Jonathan M.
Kantsadi, Anastassia L.
Vakonakis, Ioannis
author_sort Machin, Jonathan M.
collection PubMed
description BACKGROUND: Malaria kills over 400,000 people each year and nearly half the world’s population live in at-risk areas. Progress against malaria has recently stalled, highlighting the need for developing novel therapeutics. The parasite haemoglobin degradation pathway, active in the blood stage of the disease where malaria symptoms and lethality manifest, is a well-established drug target. A key enzyme in this pathway is the papain-type protease falcipain-2. METHODS: The crystallographic structure of falcipain-2 at 3.45 Å resolution was resolved in complex with an (E)-chalcone small-molecule inhibitor. The falcipain-2–(E)-chalcone complex was analysed with reference to previous falcipain complexes and their similarity to human cathepsin proteases. RESULTS: The (E)-chalcone inhibitor binds falcipain-2 to the rear of the substrate-binding cleft. This is the first structure of a falcipain protease where the rear of the substrate cleft is bound by a small molecule. In this manner, the (E)-chalcone inhibitor mimics interactions observed in protein-based falcipain inhibitors, which can achieve high interaction specificity. CONCLUSIONS: This work informs the search for novel anti-malaria therapeutics that target falcipain-2 by showing the binding site and interactions of the medically privileged (E)-chalcone molecule. Furthermore, this study highlights the possibility of chemically combining the (E)-chalcone molecule with an existing active-site inhibitor of falcipain, which may yield a potent and selective compound for blocking haemoglobin degradation by the malaria parasite.
format Online
Article
Text
id pubmed-6889325
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-68893252019-12-11 The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site Machin, Jonathan M. Kantsadi, Anastassia L. Vakonakis, Ioannis Malar J Research BACKGROUND: Malaria kills over 400,000 people each year and nearly half the world’s population live in at-risk areas. Progress against malaria has recently stalled, highlighting the need for developing novel therapeutics. The parasite haemoglobin degradation pathway, active in the blood stage of the disease where malaria symptoms and lethality manifest, is a well-established drug target. A key enzyme in this pathway is the papain-type protease falcipain-2. METHODS: The crystallographic structure of falcipain-2 at 3.45 Å resolution was resolved in complex with an (E)-chalcone small-molecule inhibitor. The falcipain-2–(E)-chalcone complex was analysed with reference to previous falcipain complexes and their similarity to human cathepsin proteases. RESULTS: The (E)-chalcone inhibitor binds falcipain-2 to the rear of the substrate-binding cleft. This is the first structure of a falcipain protease where the rear of the substrate cleft is bound by a small molecule. In this manner, the (E)-chalcone inhibitor mimics interactions observed in protein-based falcipain inhibitors, which can achieve high interaction specificity. CONCLUSIONS: This work informs the search for novel anti-malaria therapeutics that target falcipain-2 by showing the binding site and interactions of the medically privileged (E)-chalcone molecule. Furthermore, this study highlights the possibility of chemically combining the (E)-chalcone molecule with an existing active-site inhibitor of falcipain, which may yield a potent and selective compound for blocking haemoglobin degradation by the malaria parasite. BioMed Central 2019-12-02 /pmc/articles/PMC6889325/ /pubmed/31791339 http://dx.doi.org/10.1186/s12936-019-3043-0 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Machin, Jonathan M.
Kantsadi, Anastassia L.
Vakonakis, Ioannis
The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title_full The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title_fullStr The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title_full_unstemmed The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title_short The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
title_sort complex of plasmodium falciparum falcipain-2 protease with an (e)-chalcone-based inhibitor highlights a novel, small, molecule-binding site
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889325/
https://www.ncbi.nlm.nih.gov/pubmed/31791339
http://dx.doi.org/10.1186/s12936-019-3043-0
work_keys_str_mv AT machinjonathanm thecomplexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite
AT kantsadianastassial thecomplexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite
AT vakonakisioannis thecomplexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite
AT machinjonathanm complexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite
AT kantsadianastassial complexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite
AT vakonakisioannis complexofplasmodiumfalciparumfalcipain2proteasewithanechalconebasedinhibitorhighlightsanovelsmallmoleculebindingsite