Key result
A novel Suramin-derivative, compound 8, demonstrated potent in vitro inhibition of human Norovirus RNA-dependent RNA polymerase with an IC50 of 28 nM, comparable to Suramin.
A novel Suramin derivative (compound 8) demonstrates potent in vitro inhibition of Norovirus RNA-dependent RNA polymerase, providing a structural platform for future antiviral drug optimization.
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Offers a scaffold for norovirus antivirals; leaves open in vivo efficacy and safety validation.
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.
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Croci et al. (2014) studied Norovirus infection. Suramin-derivative 8 vs. Suramin was evaluated on Inhibition of human Norovirus RNA-dependent RNA polymerase (hNV-RdRp) activity (IC50). A novel Suramin-derivative, compound 8, demonstrated potent in vitro inhibition of human Norovirus RNA-dependent RNA polymerase with an IC50 of 28 nM, comparable to Suramin.
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