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TitleRational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope.
Journal, issue, pagesCell Host Microbe, Vol. 23, Issue 5, Page 618-627.e6, Year 2018
Publish dateMay 9, 2018
AuthorsKannan Tharakaraman / Satoru Watanabe / Kuan Rong Chan / Jia Huan / Vidya Subramanian / Yok Hian Chionh / Aditya Raguram / Devin Quinlan / Megan McBee / Eugenia Z Ong / Esther S Gan / Hwee Cheng Tan / Anu Tyagi / Shashi Bhushan / Julien Lescar / Subhash G Vasudevan / Eng Eong Ooi / Ram Sasisekharan /
PubMed AbstractFollowing the recent emergence of Zika virus (ZIKV), many murine and human neutralizing anti-ZIKV antibodies have been reported. Given the risk of virus escape mutants, engineering antibodies that ...Following the recent emergence of Zika virus (ZIKV), many murine and human neutralizing anti-ZIKV antibodies have been reported. Given the risk of virus escape mutants, engineering antibodies that target mutationally constrained epitopes with therapeutically relevant potencies can be valuable for combating future outbreaks. Here, we applied computational methods to engineer an antibody, ZAb_FLEP, that targets a highly networked and therefore mutationally constrained surface formed by the envelope protein dimer. ZAb_FLEP neutralized a breadth of ZIKV strains and protected mice in distinct in vivo models, including resolving vertical transmission and fetal mortality in infected pregnant mice. Serial passaging of ZIKV in the presence of ZAb_FLEP failed to generate viral escape mutants, suggesting that its epitope is indeed mutationally constrained. A single-particle cryo-EM reconstruction of the Fab-ZIKV complex validated the structural model and revealed insights into ZAb_FLEP's neutralization mechanism. ZAb_FLEP has potential as a therapeutic in future outbreaks.
External linksCell Host Microbe / PubMed:29746833 / PubMed Central
MethodsEM (single particle)
Resolution9.7 Å
Structure data

EMDB-7613:
CryoEM structure of a neutralizing antibody Fab fragment bound to Zika Virus
Method: EM (single particle) / Resolution: 9.7 Å

Source
  • Zika virus
  • Homo sapiens (human)

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