@article {Masaikemol.109.059006, author = {Yuka Masaike and Takeshi Takagi and Masataka Hirota and Joe Yamada and Satoru Ishihara and Tetsu M. C. Yung and Takamasa Inoue and Chika Sawa and Hiroshi Sagara and Satoshi Sakamoto and Yasuaki Kabe and Yasuyuki Takahashi and Yuki Yamaguchi and Hiroshi Handa}, title = {Identification of Dynamin-2-mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates}, elocation-id = {mol.109.059006}, year = {2009}, doi = {10.1124/mol.109.059006}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.059006}, eprint = {https://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.059006.full.pdf}, journal = {Molecular Pharmacology} }