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LIsTEN SIGNED

β-Lactams as flaviviral NS3 protease inhibitors

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 LIsTEN project word cloud

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

consist    near    valuable    ns3    exist    nile    purpose    culture    america    metabolic    zikv    living    derivatives    bond    compounds    incorporation    improvement    moment    coupled    medical    inhibitors    peptide    natural    wnv    cell    zika    global    electrophilic    lactams    tropical    denv    virus    infections    strategy    climate    agents    stability    synthesized    parts    mediterranean    inhibitory    act    diseases    catalytic    acids    unnatural    potent    billion    covalent    dengue    reduce    warming    off    spread    active    sub    regions    ameliorate    treatment    emerged    selectivity    lactam    people    adriatic    membrane    flaviviral    beta    outbreak    west    site    residue    disease    significantly    accordingly    inhibitor    warheads    possibility    potency    moderate    threat    coast    permeability    group    previously    assays    united    host    affinity    asia    warhead    enzyme    consequence    protease    biochemical    binding    amino    serine    moiety    replication   

Project "LIsTEN" data sheet

The following table provides information about the project.

Coordinator
RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG 

Organization address
address: SEMINARSTRASSE 2
city: HEIDELBERG
postcode: 69117
website: www.uni-heidelberg.de

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 Germany [DE]
 Project website https://www.ipmb.uni-heidelberg.de/chemie/klein/drazic.html
 Total cost 171˙460 €
 EC max contribution 171˙460 € (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 2017-05-02   to  2019-05-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG DE (HEIDELBERG) coordinator 171˙460.00

Map

 Project objective

Flaviviral infections already represent a threat to 2.5 billion people living in tropical and sub-tropical regions. As a consequence of climate change and global warming in the near future these infections are expected to spread to areas with moderate climate and the possibility of disease outbreak will exist in Europe, especially around the Mediterranean and Adriatic coast, as well as in the United States of America and large parts of Asia. At the moment no medical treatment against flaviviral diseases is available. Recently, peptide-based compounds which act as flaviviral NS3 protease inhibitors, emerged as potent agents against dengue virus (DENV), Zika virus (ZIKV) and West Nile virus (WNV). These compounds consist of two to four natural or unnatural amino acids and act by binding to the active site of the protease. Accordingly, the incorporation of an electrophilic warhead, a moiety which would facilitate the covalent binding of the inhibitor to the catalytic serine residue, into the peptide inhibitor represents a valuable strategy for the improvement of potency of such inhibitors. The goal of the proposed project is to investigate the potential of β-lactams as electrophilic warheads in DENV, ZIKV and WNV protease inhibitors. For that purpose, new β-lactam derivatives will be synthesized, coupled to peptide inhibitors previously developed by the host group and their affinity to the target will be evaluated by biochemical assays. The most potent compounds will be characterized in more detail and their activity against dengue virus replication in cell culture, off-target binding, membrane permeability and metabolic stability will be studied. We expect the formation of a covalent bond between inhibitor and active site of the enzyme to significantly improve inhibitory activity by increasing binding affinity, as well as to ameliorate selectivity and reduce off-target binding.

 Publications

year authors and title journal last update
List of publications.
2019 Tonko Dražić, Sara Kopf, James Corridan, Mila M. Leuthold, Branimir Bertoša, Christian D. Klein
Peptide-β-lactam Inhibitors of Dengue and West Nile Virus NS2B-NS3 Protease Display Two Distinct Binding Modes
published pages: 140-156, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00759
Journal of Medicinal Chemistry 63/1 2020-02-12

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