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

被引：40

作者：

Croci, Romina ^{[1
]}

Pezzullo, Margherita ^{[1
]}

Tarantino, Delia ^{[1
]}

Milani, Mario ^{[1
,2
]}

Tsay, Shwu-Chen ^{[3
]}

Sureshbabu, Radhakrishnan ^{[4
,5
]}

Tsai, Yi-Jin ^{[2
,4
,5
]}

Mastrangelo, Eloise ^{[1
]}

Rohayem, Jacques ^{[6
,7
]}

Bolognesi, Martino ^{[1
]}

Hwu, Jih Ru ^{[3
,4
,5
]}

机构：

[1] Univ Milan, Dept Biosci, Milan, Italy

[2] CNR IBF, Ist Biofis, Milan, Italy

[3] Natl Cent Univ, Dept Chem, Jhongli, Taiwan

[4] Natl Tsing Hua Univ, Dept Chem, Hsinchu, Taiwan

[5] Natl Tsing Hua Univ, Frontier Res Ctr Fundamental & Appl Sci Matters, Hsinchu, Taiwan

[6] Riboxx GmbH, Radebeul, Germany

[7] Tech Univ Dresden, Inst Virol, Dresden, Germany

来源：

PLOS ONE | 2014年 / 9卷 / 03期

关键词：

GROWTH-FACTOR; VACCINE; PATHOGENESIS; ANTAGONIST; INFECTION; RECEPTOR; PPNDS; DRUG;

D O I：

10.1371/journal.pone.0091765

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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