RT Journal Article
SR Electronic
T1 Identification of Dynamin-2-Mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 262
OP 269
DO 10.1124/mol.109.059006
VO 77
IS 2
A1 Masaike, Yuka
A1 Takagi, Takeshi
A1 Hirota, Masataka
A1 Yamada, Joe
A1 Ishihara, Satoru
A1 Yung, Tetsu M. C.
A1 Inoue, Takamasa
A1 Sawa, Chika
A1 Sagara, Hiroshi
A1 Sakamoto, Satoshi
A1 Kabe, Yasuaki
A1 Takahashi, Yasuyuki
A1 Yamaguchi, Yuki
A1 Handa, Hiroshi
YR 2010
UL http://molpharm.aspetjournals.org/content/77/2/262.abstract
AB 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.