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  • Marine alkaloid oroidin analogues with antiviral potential [Elektronski vir] : a novel class of synthetic compounds targeting the cellular chaperone Hsp90
    Lillsunde, Katja-Emilia ...
    Marine organisms and their metabolites are a diverse source of scaffolds for potential pharmacological molecular probes and, less frequently, for pharmaceutical lead compounds. In this study, 157 ... synthetic analogues of marine sponge-derived alkaloids clathrodin and oroidin were screened against replicon models of two RNA viruses, hepatitis C (HCV) and Chikungunya virus (CHIKV) as part of a larger screening project. Four compounds were found to selectively inhibit the HCV replicon (IC50 1.6-4.6 microM). These belong to the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole class of compounds originally designed to target the ATP-binding site of bacterial DNA gyrase. The ATP-binding site of this bacterial protein has high structural similarity to the ATP-binding site of heat shock protein 90 (Hsp90), a host-cell chaperone universally required for viral replication, which led us to examine inhibition of Hsp90 as the compounds' potential mechanism of action. Binding of the four hit compounds to Hsp90 was evaluated through microscale thermophoresis and molecular modelling, which supported our hypothesis of interaction with Hsp90 (Kd 18-79 microM) as basis for the compounds' antiviral activity. The presented novel structural class of small molecules that target the Hsp90 ATP-binding site has excellent potential for further antiviral drug development because of the compounds' low toxicity and synthetic accessibility.
    Vir: Chemical biology & drug design [Elektronski vir]. - ISSN 1747-0285 (Vol. 90, iss. 6, 2017, str. 1147-154)
    Vrsta gradiva - e-članek
    Leto - 2017
    Jezik - angleški
    COBISS.SI-ID - 4338545

    Povezava(-e):

    http://onlinelibrary.wiley.com/doi/10.1111/cbdd.13034/epdf
    DOI

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