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

Shen Y, Zhukovskaya NL, Zimmer MI, Soelaiman S, Bergson P, Wang CR, Gibbs CS, Tang WJ
Proc Natl Acad Sci U S A 101 3242-7 (2004)
Cited: 81 times
EuropePMC logo PMID: 14978283

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.

Reviews - 1pk0 mentioned but not cited (1)

  1. Molecular motions as a drug target: mechanistic simulations of anthrax toxin edema factor function led to the discovery of novel allosteric inhibitors. Laine E, Martínez L, Ladant D, Malliavin T, Blondel A. Toxins (Basel) 4 580-604 (2012)

Articles - 1pk0 mentioned but not cited (3)

  1. Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin. Guo Q, Shen Y, Lee YS, Gibbs CS, Mrksich M, Tang WJ. EMBO J 24 3190-3201 (2005)
  2. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Shen Y, Zhukovskaya NL, Zimmer MI, Soelaiman S, Bergson P, Wang CR, Gibbs CS, Tang WJ. Proc Natl Acad Sci U S A 101 3242-3247 (2004)
  3. Analyzing In Silico the Relationship Between the Activation of the Edema Factor and Its Interaction With Calmodulin. Pitard I, Monet D, Goossens PL, Blondel A, Malliavin TE. Front Mol Biosci 7 586544 (2020)


Reviews citing this publication (31)

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Articles citing this publication (46)

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Related citations provided by authors (1)

  1. Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins.. Shen Y, Lee YS, Soelaiman S, Bergson P, Lu D, Chen A, Beckingham K, Grabarek Z, Mrksich M, Tang WJ EMBO J 21 6721-32 (2002)

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