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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 (IC 50  = 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.

Structural Bases of Norovirus RNA Dependent RNA Polymerase Inhibition by Novel Suramin-Related Compounds