HIV LTR G-4

G-quadruplexes in the HIV-1 genome: novel targets for the development of selective antiviral drugs

Coordinatore	UNIVERSITA DEGLI STUDI DI PADOVA    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Italy [IT]
Totale costo	1˙989˙471 €
EC contributo	1˙989˙471 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2013-CoG
Funding Scheme	ERC-CG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-05-01   -   2019-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITA DEGLI STUDI DI PAVIA  Organization address address: STRADA NUOVA 65 city: PAVIA postcode: 27100 contact info Titolo: Dr. Nome: Sofia Cognome: Baggini Email: send email Telefono: 390383000000 Fax: 390383000000	IT (PAVIA)	beneficiary	659˙604.00
2	UNIVERSITA DEGLI STUDI DI PADOVA  Organization address address: VIA 8 FEBBRAIO 2 city: PADOVA postcode: 35122 contact info Titolo: Prof. Nome: Giorgio Cognome: Palù Email: send email Telefono: +39 0498272350	IT (PADOVA)	hostInstitution	1˙329˙867.00
3	UNIVERSITA DEGLI STUDI DI PADOVA  Organization address address: VIA 8 FEBBRAIO 2 city: PADOVA postcode: 35122 contact info Titolo: Prof. Nome: Sara Cognome: Richter Email: send email Telefono: +39 049 8272346 Fax: +39 049 8272355	IT (PADOVA)	hostInstitution	1˙329˙867.00

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 Obiettivo del progetto (Objective)

'G-quadruplexes (G-4) are polymorphic nucleic acid structures identified in gene promoters where they act as transcription regulators. G-4s have been found in eukaryotic and prokaryotic organisms, while very little information is available on viruses. The applicant research group has recently shown that HIV-1, which integrates into the human chromosomes and exploits cellular factors to activate transcription, takes advantage of G-4-mediated transcription regulation. G-4 disruption stimulates promoter activity while G-4 stabilization by small molecules inhibits it, showing a striking parallelism between HIV-1 LTR and eukaryotic promoter G-4s. Preliminary results indicate that similar G-4 structures form also in the viral RNA genome before retrotranscription. Available G-4 ligands, developed as anticancer drugs targeting DNA G-4, recognize both viral and cellular G-4s. Therefore, they cannot be straightforwardly used as anti-HIV compounds. The aim of this project is to develop highly specific anti-HIV-1 drugs targeting LTR DNA and/or RNA G-4s, using both reversible G-4 ligands and G-4-selective alkylating/cleaving agents, triggered by external stimuli. These approaches will be taken: a) to increase selectivity by 1) screening of ligands against LTR G-4s to select the best hits among libraries of G-4 ligands; 2) conjugation of the most promising leads to modified nucleic acids complementing LTR G-4 loop/flanking regions, to deliver the drug to its target; b) to stabilize binding by conjugation of the ligands to 3) an alkylating/cleaving subunit, and 4) an activable moiety (such as quinone methides) that alkylates the target only once the drug has reached it. Physico-chemical, biomolecular, cellular and viral assays will be used to tests the compounds. This approach should deliver reversible and irreversible ligands that selectively inhibit viral transcription and/or reverse transcription, thus preventing virus production and/or integration into the host genome.'