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RHOMBOSMALPS

Enabling malaria rhomboid proteases as drug targets: usage of molecular cookie cutters to shape novel activity assays and inhibitors.

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 RHOMBOSMALPS project word cloud

Explore the words cloud of the RHOMBOSMALPS project. It provides you a very rough idea of what is the project "RHOMBOSMALPS" about.

enzyme    hence    leads    encapsulating    species    members    difficulties    assays    strategy    mutants    directed    techniques    cutter    druggability    unfortunately    chemical    turn    expansion    sma    drug    malaria    rhomboids    isolate    changer    bottleneck    game    blood    acid    verify    falciparum    therapeutics    membrane    maleic    nanodiscs    genetic    functions    agents    physiological    styrene    invasion    rendered    protein    track    inhibitors    attractive    inviability    optimize    polymer    proteases    compounds    straightforward    environment    yielding    pfroms    therapeutic    agent    proteins    detergent    free    cells    red    stability    retain    shortcomings    intramembrane    exact    probes    rules    biological    cookie    lipid    eliminate    manipulation    potent    impractical    selective    rhomboid    candidates    molecular    date    create    causative    alternative    play    generation    serve    discovery    detergents    purification    individual    human    model    eukaryotic    function   

Project "RHOMBOSMALPS" data sheet

The following table provides information about the project.

Coordinator
KATHOLIEKE UNIVERSITEIT LEUVEN 

Organization address
address: OUDE MARKT 13
city: LEUVEN
postcode: 3000
website: www.kuleuven.be

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Belgium [BE]
 Project website http://www.verhelstlab.net/
 Total cost 160˙800 €
 EC max contribution 160˙800 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2016
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2017
 Duration (year-month-day) from 2017-10-01   to  2019-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KATHOLIEKE UNIVERSITEIT LEUVEN BE (LEUVEN) coordinator 160˙800.00

Map

 Project objective

Rhomboid proteases from P. falciparum, the causative agent of malaria, play a role in invasion of human red blood cells. The exact role of the individual members is challenging to track, because of difficulties in genetic manipulation of the P.falciparum and the inviability of some loss-of-function mutants. Hence, a chemical strategy is an attractive alternative. Unfortunately, the study of these eukaryotic rhomboids (PfROMs) has rendered impractical to date.

The bottleneck is that the current purification techniques use detergents that eliminate the physiological membrane, yielding low enzyme stability and activity. In its turn, this rules out the use of activity assays and chemical probes to study their function. Encapsulating these proteins in their lipid environment will address these shortcomings. I will develop a detergent free purification method, based on a styrene maleic acid (SMA) polymer that functions as a “molecular cookie cutter”, creating SMA-lipid-protein nanodiscs, which retain their biological properties upon purification.

Using this “molecular cookie cutter” to create lipid nanodiscs, I will isolate PfROMs and develop activity assays in order to identify and optimize novel inhibitors. The most potent and selective candidates will be evaluated in a malaria invasion model to verify the druggability of malaria rhomboids. Furthermore, these novel compounds may serve as leads for a new generation of therapeutic agents.

The straightforward expansion of our approach to other intramembrane proteases may be the game-changer for drug discovery and future therapeutics directed against rhomboids from other species.

 Publications

year authors and title journal last update
List of publications.
2018 Marta Barniol-Xicota, Steven H. L. Verhelst
Stable and Functional Rhomboid Proteases in Lipid Nanodiscs by Using Diisobutylene/Maleic Acid Copolymers
published pages: 14557-14561, ISSN: 0002-7863, DOI: 10.1021/jacs.8b08441
Journal of the American Chemical Society 140/44 2020-03-03

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