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Library-Based Discovery and Characterization of Daphnane Diterpenes as Potent and Selective HIV Inhibitors in Daphne gnidium

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InPheno AG, Basel, Switzerland
Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
§ Esperanza Medicines Foundation, Basel, Switzerland
Institute of Medical Microbiology, Department of Biomedicine, University of Basel, Basel, Switzerland
Fisher Bioservices, Allschwil, Switzerland
*Tel: +41 61 267 1425. Fax: +41 61 267 1474. E-mail: [email protected]
Cite this: J. Nat. Prod. 2012, 75, 3, 414–419
Publication Date (Web):December 8, 2011
Copyright © 2011 The American Chemical Society and American Society of Pharmacognosy

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    Despite the existence of an extended armamentarium of effective synthetic drugs to treat HIV, there is a continuing need for new potent and affordable drugs. Given the successful history of natural product based drug discovery, a library of close to one thousand plant and fungal extracts was screened for antiretroviral activity. A dichloromethane extract of the aerial parts of Daphne gnidium exhibited strong antiretroviral activity and absence of cytotoxicity. With the aid of HPLC-based activity profiling, the antiviral activity could be tracked to four daphnane derivatives, namely, daphnetoxin (1), gnidicin (2), gniditrin (3), and excoecariatoxin (4). Detailed anti-HIV profiling revealed that the pure compounds were active against multidrug-resistant viruses irrespective of their cellular tropism. Mode of action studies that narrowed the site of activity to viral entry events suggested a direct interference with the expression of the two main HIV co-receptors, CCR5 and CXCR4, at the cell surface by daphnetoxin (1).

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    1H NMR data of compounds 14, 13C NMR data of compounds 1 and 2, and 1H NMR spectrum of 1. This material is available free of charge via the Internet at

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