Structural basis of antiviral activity of a protective antibody against tick-borne encephalitis virus and structure-guided rational design of this antibody

0544944 - ÚOCHB 2022 GB eng A - Abstrakt
Baykov, I. - Chojnowski, G. - Pachl, Petr - Emelianova, L. - Moor, N. - Řezáčová, Pavlína - Lamzin, V. - Tikunova, N.
Structural basis of antiviral activity of a protective antibody against tick-borne encephalitis virus and structure-guided rational design of this antibody.
FEBS Open Bio. Wiley. Roč. 11, Suppl 1 (2021), s. 214. ISSN 2211-5463. E-ISSN 2211-5463.
[FEBS Congress, Molecules of Life: Towards New Horizons /45./. 03.07.2021-08.07.2021, online]
Institucionální podpora: RVO:61388963
Obor OECD: Biochemistry and molecular biology
https://doi.org/10.1002/2211-5463.13205

Currently, there is no specific therapeutics for the treatment oftick-borne encephalitis (TBE), while the vaccination rate in mostEuropean countries is still insufficient. To fill this gap, an anti-body-based therapeutic drug for post-exposure prophylaxis andtreatment of TBE are under development. In this study we deter-mined a structure of the antibody-antigen complex for one of theprotective antibodies against glycoprotein E (glycoE) of TBEvirus (TBEV) with a resolution of 2.6A. It was found that theantibody recognizes an epitope located on the lateral ridge of theD3 domain of glycoE, one of the most promising regions of itssurface. This epitope is highly accessible, and up to 120 antibodymolecules can simultaneously bind to the same virion. There aresome other anti-TBEV antibodies directed to this region, and thestructures for two of them are known (pdb 5O6V and 6J5G). Wefound that the orientation of the studied antibody with respect toglycoE molecule is different compared to them. We suggest thatthis may affect the mechanism of antiviral action of these anti-bodies. It was shown by molecular modeling that the studiedantibody is able to block infection not only by blocking attach-ment of virus to the cell surface, but also during intra-endosomalstages of infection via cross-linking glycoE molecules. As a result,this allows the antibody not only to block the infection with highefficiency, but also minimizes the ability of this antibody to causean antibody-dependent enhancement of infection, which makesthis antibody safer for therapeutic use. These findings are in agood agreement with the results of in vivo experiments per-formed earlier. Based of structural information we also generatedsome mutant antibody variants which possess 2–3 times higheraffinity to recombinant D3 domains of glycoE belonging toSiberian and European subtypes of TBEV.
Trvalý link: http://hdl.handle.net/11104/0321729