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

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 (K(i) = 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 approximately 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.
Authors	Yuequan Shen, Natalia L Zhukovskaya, Michael I Zimmer, Sandriyana Soelaiman, Pamela Bergson, Chyung-Ru Wang, Craig S Gibbs, Wei-Jen Tang
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 9 Pg. 3242-7 (Mar 02 2004) ISSN: 0027-8424 [Print] United States
PMID	14978283 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	Adenylyl Cyclase Inhibitors Antigens, Bacterial Antiviral Agents Bacterial Toxins Exotoxins Organophosphonates Recombinant Proteins anthrax toxin adefovir Cyclic AMP Adenylyl Cyclases Adenine adefovir dipivoxil
Topics	Adenine (analogs & derivatives, chemistry, pharmacology) Adenylyl Cyclase Inhibitors Adenylyl Cyclases (chemistry) Animals Antigens, Bacterial Antiviral Agents (chemistry, pharmacology) Bacterial Toxins Binding Sites CHO Cells Cell Line Cricetinae Cyclic AMP (metabolism) Exotoxins (antagonists & inhibitors) Hepatitis B, Chronic (drug therapy) Kinetics Models, Molecular Organophosphonates Protein Conformation Recombinant Proteins (antagonists & inhibitors) Spodoptera Transfection

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