Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection

Yuequan Shen, Natalia L. Zhukovskaya, Michael I. Zimmer, Sandriyana Soelaiman, Pamela Bergson, Chyung Ru Wang, Craig S. Gibbs, Wei Jen Tang*

*Corresponding author for this work

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Edema factor (EF), a key virulence factor in anthrax pathogenesis, has calmodulin (CaM)-activated adenylyl cyclase activity. We have found that adefovir dipivoxil, a drug approved to treat chronic infection of hepatitis B virus, effectively inhibits EF-induced cAMP accumulation and changes in cytokine production in mouse primary macrophages. Adefovir diphosphate (PMEApp), the active cellular metabolite of adefovir dipivoxil, inhibits the adenylyl cyclase activity of EF in vitro with high affinity (Ki = 27 nM). A crystal structure of EF-CaM-PMEApp reveals that the catalytic site of EF forms better van der Waals contacts and more hydrogen bonds with PMEApp than with its endogenous substrate, ATP, providing an explanation for the ≈10,000-fold higher affinity EF-CaM has for PMEApp versus ATP. Adefovir dipivoxil is a clinically approved drug that can block the action of an anthrax toxin. It can be used to address the role of EF in anthrax pathogenesis.

Original languageEnglish (US)
Pages (from-to)3242-3247
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number9
DOIs
StatePublished - Mar 2 2004

ASJC Scopus subject areas

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