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Structure-activity relationships of nucleoside analogues for inhibition of tick-borne encephalitis virus

SYSNO ASEP	0465631
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Structure-activity relationships of nucleoside analogues for inhibition of tick-borne encephalitis virus
Author(s)	Eyer, L. (CZ) Šmídková, Markéta (UOCHB-X)_{RID, ORCID} Nencka, Radim (UOCHB-X)_{RID, ORCID} Neča, J. (CZ) Kastl, T. (CZ) Palus, Martin (BC-A)_{RID, ORCID} De Clercq, E. (BE) Růžek, Daniel (BC-A)_{RID, ORCID}
Source Title	Antiviral Research. - : Elsevier - ISSN 0166-3542 Roč. 133, Sep (2016), s. 119-129
Number of pages	11 s.
Language	eng - English
Country	NL - Netherlands
Keywords	structure-activity relationship ; tick-borne encephalitis ; nucleoside inhibitor ; antiviral activity ; cytotoxicity
Subject RIV	CC - Organic Chemistry
Subject RIV - cooperation	Biology Centre (since 2006) - Microbiology, Virology
R&D Projects	NV16-34238A GA MZd - Ministry of Health (MZ)
	GA16-20054S GA ČR - Czech Science Foundation (CSF)
Institutional support	UOCHB-X - RVO:61388963 ; BC-A - RVO:60077344
UT WOS	000384856200014
EID SCOPUS	84982836748
DOI	10.1016/j.antiviral.2016.07.018
Annotation	Tick-borne encephalitis (TBE) represents one of the most serious arboviral neuro-infections in Europe and northern Asia. As no specific antiviral therapy is available at present, there is an urgent need for efficient drugs to treat patients with TBE virus (TBEV) infection. Using two standardised in vitro assay systems, we evaluated a series of 29 nucleoside derivatives for their ability to inhibit TBEV replication in cell lines of neuronal as well as extraneural origin. The series of tested compounds included 2'-C- or 2'-O-methyl substituted nucleosides, 2'-C-fluoro-2'-C-methyl substituted nucleosides, 3'-O-methyl substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase modified nucleosides and neplanocins. Our data demonstrate a relatively stringent structure-activity relationship for modifications at the 2', 3', and 4' nucleoside positions. Whereas nucleoside derivatives with the methylation at the C2' position or azido modification at the C4'position exerted a strong TBEV inhibition activity (EC50 from 0.3 to 11.1 mu M) and low cytotoxicity in vitro, substitutions of the O2' and O3' positions led to a complete loss of anti-TBEV activity (EC50 > 50 mu M). Moreover, some structural modifications of the heterobase moiety resulted in a high increase of cytotoxicity in vitro. High antiviral activity and low cytotoxicity of C2' methylated or C4' azido substituted pharmacophores suggest that such compounds might represent promising candidates for further development of potential therapeutic agents in treating TBEV infection.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2017

Number of the records: 1