Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors
Akaberi, Dario Båhlström, Amanda Chinthakindi, Praveen K Nyman, Tomas Sandström, Anja Järhult, Josef D Palanisamy, Navaneethan Lundkvist, Åke Lennerstrand, Johan
Akaberi, Dario
Båhlström, Amanda
Chinthakindi, Praveen K
Nyman, Tomas
Sandström, Anja
Järhult, Josef D
Palanisamy, Navaneethan
Lundkvist, Åke
Lennerstrand, Johan
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EPub Date
Publication Date
2021-04-16
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Abstract
Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC<sub>50</sub> = 0.92 μM in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC<sub>50</sub> = 0.25 μM. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.
Citation
Akaberi, D., Båhlström, A., Chinthakindi, P. K., Nyman, T., Sandström, A., Järhult, J. D., Palanisamy, N., Lundkvist, Å., & Lennerstrand, J. (2021). Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors. Antiviral Research, 190, 105074.
Publisher
Elsevier
Journal
Antiviral Research
Research Unit
DOI
10.1016/j.antiviral.2021.105074
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
Series/Report no.
ISSN
0166-3542
EISSN
1872-9096
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Sponsors
Kjell and Märta Beijer Foundation and European Union's Horizon 2020 research and innovation program