Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection
| Autor: | Natalia L. Zhukovskaya, Sandriyana Soelaiman, Wei-Jen Tang, Chyung Ru Wang, Craig S. Gibbs, Yuequan Shen, Pamela Bergson, Michael Zimmer |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Calmodulin Protein Conformation Anthrax toxin Bacterial Toxins Organophosphonates Exotoxins CHO Cells Spodoptera medicine.disease_cause Transfection Antiviral Agents Virus Virulence factor Cell Line Adenylyl cyclase Pathogenesis chemistry.chemical_compound Hepatitis B Chronic Cricetinae Adefovir medicine Cyclic AMP Animals Hepatitis B virus Antigens Bacterial Multidisciplinary Binding Sites biology Adenine Biological Sciences Virology Recombinant Proteins Kinetics chemistry Adenylyl Cyclase Inhibitors biology.protein medicine.drug Adenylyl Cyclases |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 101(9) |
| ISSN: | 0027-8424 |
| Popis: | 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 ≈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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|