PT  - JOURNAL ARTICLE
AU  - Yuka Masaike
AU  - Takeshi Takagi
AU  - Masataka Hirota
AU  - Joe Yamada
AU  - Satoru Ishihara
AU  - Tetsu M. C. Yung
AU  - Takamasa Inoue
AU  - Chika Sawa
AU  - Hiroshi Sagara
AU  - Satoshi Sakamoto
AU  - Yasuaki Kabe
AU  - Yasuyuki Takahashi
AU  - Yuki Yamaguchi
AU  - Hiroshi Handa
TI  - Identification of Dynamin-2-mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates
AID  - 10.1124/mol.109.059006
DP  - 2009 Jan 01
TA  - Molecular Pharmacology
PG  - mol.109.059006
4099  - http://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.059006.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.059006.full
AB  - Nitrogen-containing bisphosphonates are pyrophosphate analogues that have long been the preferred prescription for treating osteoporosis. While these drugs are considered inhibitors of prenylation and are thought to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation appears to be insufficient. As other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, here we first investigated 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. Evidence is presented 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.The American Society for Pharmacology and Experimental Therapeutics