Abstract
The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.
Highlights
The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs
The active site of the ZIKV non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is located above the palm and is surrounded by loops protruding from both thumb and palm domains, likely to be involved in the stabilization of the RNA molecules during the extension (Fig. 1a)
Similar to dengue viruses (DENV), the ZIKV NS5 RdRp binds to two Zn þ 2 ions, one at the finger (G439, H443, C448 and C451) and the other at the thumb (H714, C730, C849) domain (Fig. 2)
Summary
The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. The priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution. The flaviviral non-structural protein 5 RNA-dependent RNA-polymerase (NS5 RdRp) has a central role in virus genome replication and is absent in the mammalian hosts, being extensively targeted for drug discovery and development[4]. Several groups reported the discovery of novel RdRp inhibitors with pan-serotype activity against dengue viruses (DENV) In these cases, the use of X-ray crystallographic structures was fundamental to develop optimized lead candidates[7,8]. We describe the crystal structure of the ZIKV NS5 RdRp domain and compare it with the homologous dengue virus proteins from different serotypes to identify suitable target sites for anti-ZIKV drug discovery and elucidate their structural drug-binding features
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