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

• DOI: 10.1073/pnas.0306552101
• Publication Date: 2004-03-03T02:33:11Z
• Authors: Yuequan Shen; Natalia L. Zhukov...; Michael I. Zimmer; Sandriyana Soelaiman; Pamela Bergson; Chyung-Ru Wang; Craig S. Gibbs; Wei-Jen Tang
• Keywords: Adefovir; Anthrax toxin; Virulence factor

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