Anno2014
AutoriCroci, Romina; Pezzullo, Margherita; Tarantino, Delia; Milani, Mario; Tsay, Shwuchen; Sureshbabu, Radhakrishnan; Tsai, Yijin; Mastrangelo, Eloise; Rohayem, Jacques; Bolognesi, Martino C.; Hwu, Jihru
AbstractNoroviruses (NV) are +ssRNA viruses responsible for severe gastroenteritis; no effective vaccines/antivirals are currently available. We previously identified Suramin (9) as a potent inhibitor of NV-RNA dependent RNA polymerase (NV-RdRp). Despite significant in vitro activities versus several pharmacological targets, Suramin clinical use is hampered by pharmacokinetics/toxicity problems. To improve Suramin access to NV-RdRp in vivo, a Suramin-derivative, 8, devoid of two sulphonate groups, was synthesized, achieving significant anti-human-NV-RdRp activity (IC50 = 28 nM); the compound inhibits also murine NV (mNV) RdRp. The synthesis process led to the isolation/characterization of lower molecular weight intermediates (3-7) hosting only one sulphonate head. The crystal structures of both hNV/mNV-RdRps in complex with 6, were analyzed, providing new knowledge on the interactions that a small fragment can establish with NV-RdRps, and establishing a platform for structure-guided optimization of potency, selectivity and drugability.
RivistaPlos One
ISSN1932-6203
Impact factor0
Volume9
Pagina inizio
Pagina fine
Autori IBFEloise MASTRANGELO, Mario MILANI, Delia TARANTINO
Linee di Ricerca IBFMD.P01.005.001
Sedi IBFIBF.MI