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Antimicrobial Agents and Chemotherapy, March 2004, p. 867-872, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.867-872.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 In Vitro

Yu-Huan Li,1 Pei-Zhen Tao,1* Yu-Zhen Liu,1 and Jian-Dong Jiang1,2

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,1 Division of Medical Oncology, Mount Sinai School of Medicine, New York, New York 100292

Received 22 July 2003/ Returned for modification 18 September 2003/ Accepted 13 November 2003

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 µM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 µM. The therapeutic index of GA was over 3,700 (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 G1/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.

* Corresponding author. Mailing address for Jian-Dong Jiang: Division of Medical Oncology, Mount Sinai School of Medicine, New York, N.Y. 10029. Phone. (212) 241-6441. Fax: (212) 996-9801. E-mail: jiandong.jiang{at}mssm.edu. Mailing address for Pei-Zhen Tao: Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Tian-Tan-Xi-Li, Beijing, 100050, P.R. China. Phone: 86-10-63167255. Fax: 86-10-63017302. E-mail: pztao{at}public3.bta.net.cn.

Antimicrobial Agents and Chemotherapy, March 2004, p. 867-872, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.867-872.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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