Cel 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. Dziedzina nauki natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsnatural sciencesbiological sciencesmicrobiologyvirologynatural sciencesbiological sciencesgeneticsRNAnatural sciencesbiological sciencesgeneticsgenomesmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals Program(-y) 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) Temat(-y) ERC-CG-2013-LS7 - ERC Consolidator Grant - Diagnostic Tools, Therapies and Public Health Zaproszenie do składania wniosków ERC-2013-CoG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-CG - ERC Consolidator Grants Instytucja przyjmująca UNIVERSITA DEGLI STUDI DI PADOVA Wkład UE € 1 329 867,00 Adres VIA 8 FEBBRAIO 2 35122 Padova Włochy Zobacz na mapie Region Nord-Est Veneto Padova Rodzaj działalności Higher or Secondary Education Establishments Kierownik naukowy Sara Richter (Prof.) Kontakt administracyjny Monica Vettore (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych Beneficjenci (2) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko UNIVERSITA DEGLI STUDI DI PADOVA Włochy Wkład UE € 1 329 867,00 Adres VIA 8 FEBBRAIO 2 35122 Padova Zobacz na mapie Region Nord-Est Veneto Padova Rodzaj działalności Higher or Secondary Education Establishments Kierownik naukowy Sara Richter (Prof.) Kontakt administracyjny Monica Vettore (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych UNIVERSITA DEGLI STUDI DI PAVIA Włochy Wkład UE € 659 604,00 Adres STRADA NUOVA 65 27100 Pavia Zobacz na mapie Region Nord-Ovest Lombardia Pavia Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Sofia Baggini (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
