MEPHITIS

Targeting Protein Synthesis in the Apicoplast and Cytoplasm of Plasmodium

 Coordinatore FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA) 

 Organization address address: CARRER BALDIRI REIXAC 10-12 PARC SCIENTIFIC DE BARCELONA
city: BARCELONA
postcode: 8028

contact info
Titolo: Ms.
Nome: Adriana
Cognome: Grosu
Email: send email
Telefono: +34 934 020 450
Fax: +34 93 403 71 14

 Nazionalità Coordinatore Spain [ES]
 Totale costo 3˙253˙380 €
 EC contributo 2˙145˙151 €
 Programma FP7-HEALTH
Specific Programme "Cooperation": Health
 Code Call FP7-HEALTH-2007-B
 Funding Scheme CP-SICA
 Anno di inizio 2009
 Periodo (anno-mese-giorno) 2009-01-01   -   2012-06-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)

 Organization address address: CARRER BALDIRI REIXAC 10-12 PARC SCIENTIFIC DE BARCELONA
city: BARCELONA
postcode: 8028

contact info
Titolo: Ms.
Nome: Adriana
Cognome: Grosu
Email: send email
Telefono: +34 934 020 450
Fax: +34 93 403 71 14

ES (BARCELONA) coordinator 741˙489.00
2    FUNDACIO PRIVADA PARC CIENTIFIC DE BARCELONA

 Organization address address: Baldiri i Reixac, 10-12
city: BARCELONA
postcode: 8028

contact info
Titolo: Dr.
Nome: Miriam
Cognome: Royo Expósito
Email: send email
Telefono: -4037181
Fax: -4037168

ES (BARCELONA) participant 329˙256.00
3    COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

 Organization address address: Anusandhan Bhawan, Rafi Marg 2
city: NEW DEHLI
postcode: 110001

contact info
Titolo: Dr.
Nome: Saman
Cognome: Habib
Email: send email
Telefono: 91-522-2612411 Ext.4282
Fax: 91-522-2623405

IN (NEW DEHLI) participant 298˙170.00
4    CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

 Organization address address: Rue Michel -Ange 3
city: PARIS
postcode: 75794

contact info
Titolo: Mr.
Nome: Philippe
Cognome: Pieri
Email: send email
Telefono: +33 3 88106310
Fax: +33 3 88106095

FR (PARIS) participant 269˙530.00
5    UNIVERSIDADE DE AVEIRO

 Organization address address: CAMPO UNIVERSITARIO DE SANTIAGO
city: AVEIRO
postcode: 3810-193

contact info
Titolo: Prof.
Nome: Manuel António Da Silva
Cognome: Santos
Email: send email
Telefono: 351234000000
Fax: 351234000000

PT (AVEIRO) participant 259˙056.00
6    INTERNATIONAL CENTRE FOR GENETIC ENGINEERING AND BIOTECHNOLOGY

 Organization address address: PADRICIANO 99
city: TRIESTE
postcode: 34149

contact info
Titolo: Mr.
Nome: Decio
Cognome: Ripandelli
Email: send email
Telefono: -3757338
Fax: -3757364

IT (TRIESTE) participant 151˙650.00
7    ISTITUTO SUPERIORE DI SANITA

 Organization address address: Viale Regina Elena 299
city: ROMA
postcode: 161

contact info
Titolo: Dr.
Nome: Rosa Maria
Cognome: Martoccia
Email: send email
Telefono: 390650000000
Fax: 390650000000

IT (ROMA) participant 96˙000.00
8    UNIVERSITY OF MELBOURNE

 Organization address address: PARKVILLEOFFICE OF THE VICE CHANCELLOR
city: MELBOURNE
postcode: 3010

contact info
Titolo: Ms.
Nome: Boland
Cognome: Alice
Email: send email
Telefono: +61 3 8344 2052
Fax: +61 3 9347 6739

AU (MELBOURNE) participant 0.00

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

directed    therapeutic    transfer    enzyme    protein    malarial    title    parasite    inhibitory    synthesis    arss    data    unveiled    contains    trna    translation    families    machinery    falciparum    ribosome    molecules    anti    biology    apicoplast    cellular    mephitis    article    ars    antimalarial    malaria    words    components    drug    plasmodium    rna    structural    drugs    pubmed   

 Obiettivo del progetto (Objective)

'The protein synthesis machinery represents one of the most useful targets for the development of new anti-infectives. Several families of broadly used antibiotics (tetracyclines, macrolides, and novel glycopeptides like vancomycin, among others) exert their function by blocking the protein synthesis machinery. Doxicycline, a tetracycline antibiotic, remains a useful tool for the prevention of paludism among travellers, despite its numerous secondary effects. And yet, very little is known about the specifics of the protein synthesis machinery in Plasmodium. A search of articles in the PubMed library with the words Plasmodium and ribosome/ribosomal in their titles will yield 6 publications since the year 2000. Only one article contains the words tRNA (or transfer RNA) and Plasmodium in its title, in the same period. And only one article in PubMed (Snewin et al., 1996) contains the words Plasmodium and ‘tRNA synthetase’ (or ligase) in its title. This lack of information about this central metabolic pathway in Plasmodium clearly blocks the possibility of transferring the knowledge in protein synthesis to the development of new anti-malarial drugs directed against the translational machinery of the parasite. Thus, the study of components of the genetic code in Plasmodium has the potential for providing new and important information on the biology of the parasite and, more importantly, open new leads for the development of novel anti-malarials. This proposal coordinates an effort to study tRNA biology in Plasmodium falciparum. It contains specific schemes for the development of new pharmacological screens, several initiatives for the selection of new potential anti-malarial drugs, and projects designed to answer fundamental questions regarding protein synthesis in Plasmodium. The laboratories in MEPHITIS accumulate a large body of experience in the biology of this parasite, and in different aspects of tRNA biology in model species.'

Introduzione (Teaser)

A European study pursued a new avenue in the design of drugs against malaria: it explored gene translation in the parasite Plasmodium falciparum as the target.

Descrizione progetto (Article)

Malaria remains a serious health issue in certain parts of the world. Current treatment is based on a combinatorial administration of antimalarial drugs. This is only partly effective and is unfortunately associated with increased drug-resistance. Novel targeted drugs are urgently required against the causative agent Plasmodium falciparum.

The EU-funded http://www.mephitis.eu/ (MEPHITIS) (Targeting protein synthesis in the apicoplast and cytoplasm of Plasmodium) project embarked on antimalarial drug discovery. Their innovative approach targeted the parasite protein synthesis machinery.

To achieve this, researchers had to first study protein synthesis in Plasmodium and then identify molecules that could serve as therapeutic targets for malaria. Project activities concentrated on the apicoplast, a Plasmodium-specific cellular compartment that constitutes an excellent target for the development of new drugs. Of particular interest was the analysis of two different enzyme families: the aminoacyl-tRNA synthetases (ARS) and the elongation factors that are implicated in protein synthesis.

The consortium followed both a computational and structural approach in the analysis of protein synthesis components. Emphasis was also given to the study of the evolutionary relationships among ARSs, because this is an obligate step to the identification of the best candidates for future drug development.

MEMPHITIS successfully characterised the cellular distribution and the biological activity of several components of the protein synthesis apparatus of the parasite. They obtained structural data for various ARS enzymes and unveiled a new transfer RNA (tRNA) binding protein responsible for the transport of exogenous tRNAs into the parasite. This data served as the basis for the design of novel inhibitory scaffolds directed against different ARSs. Furthermore, other factors required for translation initiation, peptide release, and ribosome recycling in apicoplast and mitochondria of the Plasmodium were identified.

Efforts at validating the ability of known enzyme inhibitors to specifically inhibit parasite translation unveiled the compound borrelidin with a powerful anti-malarial activity. New inhibitory molecules have also been identified opening up novel paths for therapeutic exploitation in malaria research.

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