Abstract
The Zika virus (ZIKV) has emerged as a major health hazard. We present here a high resolution structure (1.55 Å) of ZIKV NS5 methyltransferase bound to a novel S-adenosylmethionine (SAM) analog in which a 4-fluorophenyl moiety substitutes for the methyl group. We show that the 4-fluorophenyl moiety extends into a portion of the RNA binding tunnel that typically contains the adenosine 2′OH of the RNA-cap moiety. Together, the new SAM analog and the high-resolution crystal structure are a step towards the development of antivirals against ZIKV and other flaviviruses.
Highlights
The Zika virus (ZIKV) belongs to the Flavivirus genus that includes mosquito-borne human pathogens such as dengue virus (DENV1-4), Murray Valley encephalitis virus (MVEV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), among others[1]
We show that the 4-fluorophenyl moiety extends into a portion of the RNA binding tunnel that typically contains the adenosine 2′OH of the cap-0 structure (N7MeGpppA2′OH-RNA)
We designed MS2042 on the basis of recent high resolution structures of the ZIKV NS5-MTase bound to SAM alone (NS5-MTaseSAM), or to both SAM and the 5′cap mimic 7-methyl guanosine diphosphate (7-MeGpp, NS5-MTaseSAM,7-MeGpp)[12]
Summary
The Zika virus (ZIKV) belongs to the Flavivirus genus that includes mosquito-borne human pathogens such as dengue virus (DENV1-4), Murray Valley encephalitis virus (MVEV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), among others[1]. The 5′-cap (N7MeGpppA2′OMe; where Me is a methyl group) is formed by the activities of two enzymes: NS3 that encodes a protease and helicase, and NS5 that encodes a methyltransferase (NS5-MTase) and an RNA dependent RNA polymerase. Defects in 2′O methylation attenuate the virus and is a basis for vaccine development[10, 11]. Together, these features make ZIKV NS5-MTase an attractive target for the development of antivirals. We show that the 4-fluorophenyl moiety extends into a portion of the RNA binding tunnel that typically contains the adenosine 2′OH of the cap-0 structure (N7MeGpppA2′OH-RNA). The new SAM analog and the high-resolution crystal structure provide a path for further drug development
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