PLoS ONE 2014-01-01

Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.

Romina Croci, Margherita Pezzullo, Delia Tarantino, Mario Milani, Shwu-Chen Tsay, Radhakrishnan Sureshbabu, Yi-Jin Tsai, Eloise Mastrangelo, Jacques Rohayem, Martino Bolognesi, Jih Ru Hwu

Index: PLoS ONE 9(3) , e91765, (2014)

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Abstract

Noroviruses (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.