Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope
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 co...
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/141659 |
| _version_ | 1826117370863681536 |
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| author | Tharakaraman, Kannan Watanabe, Satoru Chan, Kuan Rong Huan, Jia Subramanian, Vidya Chionh, Yok Hian Raguram, Aditya Quinlan, Devin McBee, Megan Ong, Eugenia Z. Gan, Esther S. Tan, Hwee Cheng Tyagi, Anu Bhushan, Shashi Lescar, Julien Vasudevan, Subhash G. Ooi, Eng Eong Sasisekharan, Ram |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Tharakaraman, Kannan Watanabe, Satoru Chan, Kuan Rong Huan, Jia Subramanian, Vidya Chionh, Yok Hian Raguram, Aditya Quinlan, Devin McBee, Megan Ong, Eugenia Z. Gan, Esther S. Tan, Hwee Cheng Tyagi, Anu Bhushan, Shashi Lescar, Julien Vasudevan, Subhash G. Ooi, Eng Eong Sasisekharan, Ram |
| author_sort | Tharakaraman, Kannan |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:26:12Z |
| format | Journal Article |
| id | ntu-10356/141659 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:26:12Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1416592020-06-10T01:50:20Z Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope Tharakaraman, Kannan Watanabe, Satoru Chan, Kuan Rong Huan, Jia Subramanian, Vidya Chionh, Yok Hian Raguram, Aditya Quinlan, Devin McBee, Megan Ong, Eugenia Z. Gan, Esther S. Tan, Hwee Cheng Tyagi, Anu Bhushan, Shashi Lescar, Julien Vasudevan, Subhash G. Ooi, Eng Eong Sasisekharan, Ram School of Biological Sciences Science::Biological sciences Antibody Therapeutic 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. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) 2020-06-10T01:50:19Z 2020-06-10T01:50:19Z 2018 Journal Article Tharakaraman, K., Watanabe, S., Chan, K. R., Huan, J., Subramanian, V., Chionh, Y. H., . . . Sasisekharan, R. (2018). Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope. Cell Host & Mricrobe, 23(5), 618-627.e6. doi:10.1016/j.chom.2018.04.004 1931-3128 https://hdl.handle.net/10356/141659 10.1016/j.chom.2018.04.004 29746833 2-s2.0-85046170268 5 23 618 627.e6 en Cell Host & Microbe © 2018 Elsevier Inc. All rights reserved. |
| spellingShingle | Science::Biological sciences Antibody Therapeutic Tharakaraman, Kannan Watanabe, Satoru Chan, Kuan Rong Huan, Jia Subramanian, Vidya Chionh, Yok Hian Raguram, Aditya Quinlan, Devin McBee, Megan Ong, Eugenia Z. Gan, Esther S. Tan, Hwee Cheng Tyagi, Anu Bhushan, Shashi Lescar, Julien Vasudevan, Subhash G. Ooi, Eng Eong Sasisekharan, Ram Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title | Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title_full | Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title_fullStr | Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title_full_unstemmed | Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title_short | Rational engineering and characterization of an mAb that neutralizes Zika virus by targeting a mutationally constrained quaternary epitope |
| title_sort | rational engineering and characterization of an mab that neutralizes zika virus by targeting a mutationally constrained quaternary epitope |
| topic | Science::Biological sciences Antibody Therapeutic |
| url | https://hdl.handle.net/10356/141659 |
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