Geldanamycin, a ligand of heat shock protein 90, inhibits the replication of herpes simplex virus type 1 in vitro.
Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 microM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 microM. The therapeutic index of GA was over 3700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G(1)/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1(+) cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.
Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Yu-Huan
YH
Li
Pei-Zhen
PZ
Tao
Yu-Zhen
YZ
Liu
Jian-Dong
JD
Jiang
D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents; D016227:Benzoquinones; D015139:Blotting, Southern; D002453:Cell Cycle; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics; D047029:Lactams, Macrocyclic; D008024:Ligands; D019384:Nucleic Acid Synthesis Inhibitors; D010957:Plasmids / Q000235:genetics; D011809:Quinones / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D019384:Nucleic Acid Synthesis Inhibitors; D011809:Quinones; D013937:Thymidine Kinase; C001277:geldanamycin