Antiviral activity of porphyrins and porphyrin-like compounds against tick-borne encephalitis virus: Blockage of the viral entry/fusion machinery by photosensitization-mediated destruction of the viral envelope.

Autor: Holoubek J; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500, Brno, Czech Republic., Salát J; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500, Brno, Czech Republic., Kotouček J; Department of Pharmacology and Toxicology, Veterinary Research Institute, CZ-62100, Brno, Czech Republic., Kastl T; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic., Vancová M; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005, Ceske Budejovice, Czech Republic; Faculty of Science, University of South Bohemia, CZ-37005, Ceske Budejovice, Czech Republic., Huvarová I; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic., Bednář P; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500, Brno, Czech Republic; Faculty of Science, University of South Bohemia, CZ-37005, Ceske Budejovice, Czech Republic., Bednářová K; Department of Biophysics of Nucleic Acids, Institute of Biophysics of the Czech Academy of Sciences, CZ-61200, Brno, Czech Republic., Růžek D; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500, Brno, Czech Republic., Renčiuk D; Department of Biophysics of Nucleic Acids, Institute of Biophysics of the Czech Academy of Sciences, CZ-61200, Brno, Czech Republic., Eyer L; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500, Brno, Czech Republic. Electronic address: ludek.eyer@vri.cz.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2024 Jan; Vol. 221, pp. 105767. Date of Electronic Publication: 2023 Nov 30.
DOI: 10.1016/j.antiviral.2023.105767
Abstrakt: Tick-borne encephalitis virus (TBEV), the causative agent of tick-borne encephalitis (TBE), is a medically important flavivirus endemic to the European-Asian continent. Although more than 12,000 clinical cases are reported annually worldwide, there is no anti-TBEV therapy available to treat patients with TBE. Porphyrins are macrocyclic molecules consisting of a planar tetrapyrrolic ring that can coordinate a metal cation. In this study, we investigated the cytotoxicity and anti-TBEV activity of a large series of alkyl- or (het)aryl-substituted porphyrins, metalloporphyrins, and chlorins and characterized their molecular interactions with the viral envelope in detail. Our structure-activity relationship study showed that the tetrapyrrole ring is an essential structural element for anti-TBEV activity, but that the presence of different structurally distinct side chains with different lengths, charges, and rigidity or metal cation coordination can significantly alter the antiviral potency of porphyrin scaffolds. Porphyrins were demonstrated to interact with the TBEV lipid membrane and envelope protein E, disrupt the TBEV envelope and inhibit the TBEV entry/fusion machinery. The crucial mechanism of the anti-TBEV activity of porphyrins is based on photosensitization and the formation of highly reactive singlet oxygen. In addition to blocking viral entry and fusion, porphyrins were also observed to interact with RNA oligonucleotides derived from TBEV genomic RNA, indicating that these compounds could target multiple viral/cellular structures. Furthermore, immunization of mice with porphyrin-inactivated TBEV resulted in the formation of TBEV-neutralizing antibodies and protected the mice from TBEV infection. Porphyrins can thus be used to inactivate TBEV while retaining the immunogenic properties of the virus and could be useful for producing new inactivated TBEV vaccines.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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