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Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide

Abstract

Zika virus is a mosquito-borne virus that is associated with neurodegenerative diseases, including Guillain–Barré syndrome1 and congenital Zika syndrome2. As Zika virus targets the nervous system, there is an urgent need to develop therapeutic strategies that inhibit Zika virus infection in the brain. Here, we have engineered a brain-penetrating peptide that works against Zika virus and other mosquito-borne viruses. We evaluated the therapeutic efficacy of the peptide in a lethal Zika virus mouse model exhibiting systemic and brain infection. Therapeutic treatment protected against mortality and markedly reduced clinical symptoms, viral loads and neuroinflammation, as well as mitigated microgliosis, neurodegeneration and brain damage. In addition to controlling systemic infection, the peptide crossed the blood–brain barrier to reduce viral loads in the brain and protected against Zika-virus-induced blood–brain barrier injury. Our findings demonstrate how engineering strategies can be applied to develop peptide therapeutics and support the potential of a brain-penetrating peptide to treat neurotropic viral infections.

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Fig. 1: LEAD concept facilitates engineering and biophysical characterization of antiviral AH-D peptide.
Fig. 2: AH-D peptide protects against lethal ZIKV infection in primary neuronal cells and exhibits antiviral activity in vitro.
Fig. 3: Therapeutic activity of AH-D peptide abrogates lethal ZIKV infection in mice.
Fig. 4: AH-D peptide inhibits ZIKV infection in mouse brain and preserves BBB integrity.

Data availability

Data supporting the findings of this study are available within the Article and its Supplementary Information files and from the corresponding author upon reasonable request. The data sets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Research Foundation of Singapore through an NRF Fellowship grant (NRF-NRFF2011-01), a Competitive Research Programme grant (NRF-CRP10-2012-07) and a Proof-of-Concept grant (NRF2015NRF-POC0001-19), the National Medical Research Council of Singapore (NMRC/CBRG/0005/2012) and the Centre for Precision Biology at Nanyang Technological University. This work also received support from the National Institute of Science and Technology in Dengue and Host-microorganism Interaction (INCT dengue), which is a programme sponsored by the Brazilian National Science Council (CNPq, Brazil) and the Minas Gerais Foundation for Science (FAPEMIG, Brazil). This work also received support from Financiadora de Estudos ePesquisa (FINEP 01.16.0050.00, Brazil), PP SUS: APQ-03744-17 and Comissao de Apoio a Pessoal de Ensino Superior (CAPES, Brazil). I. Marcal, T. Colina, G. dos Santos and F. Assis are acknowledged for technical assistance with experiments. The authors also acknowledge G. Batista Menezes and M. Mota Antunes for help with the acquisition of confocal microscopy images.

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J.A.J., V.V.C., M.M.T. and N.-J.C. planned the studies. J.A.J., V.V.C., S.P., A.L.C.V.R., P.L.C., J.H.P, I.O.G., T.P.M., J.L.B., V.F.Q., C.M.Q-J., G.F., D.G.S., F.M.R., A.R.F., B.K.Y. and E.W. conducted experiments. J.A.J., V.V.C., S.P., D.G.S., F.M.R., B.D.S., M.M.T. and N.-J.C. interpreted the results. J.A.J. and N.-J.C. wrote the first draft of the paper. M.M.T., F.M.R. and N.-J.C. obtained funding. All authors reviewed, edited and approved the paper.

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Correspondence to Nam-Joon Cho.

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Competing interests

N.-J.C. is a co-inventor on US patent no. 8,728,793. The other authors declare no competing interests.

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Supplementary Figures 1–15, Supplementary Tables 1–6

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Jackman, J.A., Costa, V.V., Park, S. et al. Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide. Nature Mater 17, 971–977 (2018). https://doi.org/10.1038/s41563-018-0194-2

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