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.

Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds / R. Croci, M. Pezzullo, D. Tarantino, M. Milani, S. Tsay, R. Sureshbabu, Y. Tsai, E. Mastrangelo, J. Rohayem, M. Bolognesi, J.R. Hwu. - In: PLOS ONE. - ISSN 1932-6203. - 9:3(2014 Mar 09), pp. e91765.1-e91765.10.

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

R. Croci
Primo
;
M. Pezzullo
Secondo
;
D. Tarantino;E. Mastrangelo;M. Bolognesi;
2014-03-09

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.
antuvirals ; norovirus ; RNA-dependent RNA polymerase ; structural biology ; drug design
Settore BIO/10 - Biochimica
Article (author)
File in questo prodotto:
File Dimensione Formato  
fetchObject.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 656.46 kB
Formato Adobe PDF
656.46 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/238647
Citazioni
  • ???jsp.display-item.citation.pmc??? 25
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 33
social impact