Abstract
Nitrogen-containing bisphosphonates are pyrophosphate analogs that have long been the preferred prescription for treating osteoporosis. Although these drugs are considered inhibitors of prenylation and are believed to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation seems to be insufficient. Because other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, we first investigated here the effects of bisphosphonates on simian virus 40 and adenovirus infections and, to our surprise, found that viral infections are suppressed by bisphosphonates through a prenylation-independent pathway. By in-house affinity-capture techniques, dynamin-2 was identified as a new molecular target of bisphosphonates. We present evidence that certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2. Hence, this study has uncovered a previously unknown mechanism of action of bisphosphonates and offers potential novel use for these drugs.
Footnotes
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This study was supported by Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency [Grant KH217001]; and a Grant from the Global COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant A-04].
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.059006
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ABBREVIATIONS:
- BP
- bisphosphonate
- ALN
- alendronate
- CPZ
- chlorpromazine
- DTT
- dithiothreitol
- DYN2
- dynamin-2
- ETI
- etidronate
- FPPS
- farnesyl diphosphate synthase
- GED
- GTPase effector domain
- GGOH
- geranylgeraniol
- LOV
- lovastatin
- N-BP
- nitrogen-containing bisphosphonate
- NN-BP
- non–nitrogen-containing bisphosphonate
- PC
- phosphatidylcholine
- PH
- Pleckstrin homology
- PIP3
- phosphatidylinositol (3,4,5)-triphosphate
- PMSF
- phenylmethylsulfonyl fluoride
- PRD
- proline-arginine-rich domain
- SNX9
- sorting nexin 9
- SUV
- small unilamellar vesicle
- SV40
- simian virus 40
- ZOL
- zoledronate
- PAGE
- polyacrylamide gel electrophoresis
- FBS
- fetal bovine serum
- GST
- glutathione transferase
- BZA-5B
- 2-amino-3-mercaptopropionate-(N-methyl)-3-amino-1-carboxymethyl-5-phenyl-benzodiazepine
- FTI-277
- N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt.
- Received June 30, 2009.
- Accepted November 9, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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