As Zika virus spreads throughout the world, the call for rapid development of therapeutics to treat Zika virus rings loud and clear. Taking a step further in identifying a possible therapeutic candidate, a team of researchers at Duke-NUS Medical School (Duke-NUS), in collaboration with scientists from the University of North Carolina, have discovered the mechanism by which C10, a human antibody previously identified to react with the Dengue virus, prevents Zika virus infection at a cellular level.
|C10 antibody (purple) visualized to be interacting with
the Zika virus coat (green). Credit:Victor Kostyuchenko,
Duke-NUS Medical School
Using a method called cryoelectron microscopy, which allows for the visualization of extremely small particles and their interactions, the team visualized C10 interacting with the Zika virus under different pHs, so as to mimic the different environments both the antibody and virus will find themselves in throughout infection. They showed that C10 binds to the main protein that makes up the Zika virus coat, regardless of pH, and locks these proteins into place, preventing the structural changes required for the fusion step of infection. Without fusion of the virus to the endosome, viral DNA is prevented from entering the cell, and infection is thwarted.
“Hopefully, these results will further accelerate the development of C10 as a Zika virus therapy to combat its effects of microcephaly and Guillain-Barré syndrome. This should emphasise the need for further studies of the effect of C10 on Zika virus infection in animal models,” commented Dr Lok.
“By defining the structural basis for neutralization, these studies provide further support for the idea that this antibody will protect against Zika virus infection, potentially leading to a new therapy to treat this dreaded disease,” says Ralph Baric, PhD, professor in the Department of Epidemiology at UNC’s Gillings School of Global Public Health.
These findings suggest that C10 may be developed as a therapy for Zika virus infection, and should be further explored. In addition, disrupting fusion with C10 may prove to be more effective in preventing Zika virus infection compared with therapies that attempt to disrupt docking. This is because the fusion step is critical for Zika virus infection, while the virus may develop other mechanisms to overcome disruptions to the docking step. With the call for rapid development of Zika therapies, C10 has emerged as a front runner to answer this call.
Citation: “Neutralization mechanism of a highly potent antibody against Zika virus”. Shuijun Zhang, Victor A. Kostyuchenko, Thiam-Seng Ng, Xin-Ni Lim, Justin S. G. Ooi, Sebastian Lambert, Ter Yong Tan, Douglas G. Widman, Jian Shi, Ralph S. Baric & Shee-Mei Lok. Nature Communications 2016 vol: 7 pp: 13679.
Research funding: Singapore Ministry of Education, National Research Foundation, Singapore Ministry of Health, National Institutes of Health.
Adapted from press release by Duke-NUS Medical School.