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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.

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

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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