Synthesis and biological evaluation of heat-shock protein 90 inhibitors: geldanamycin derivatives with broad antiviral activities.
BACKGROUND
Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives.


METHODS
A series of 17-substituted and 17-,19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus.


RESULTS
Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds.


CONCLUSIONS
Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity.
Li
Yan-Ping
YP
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shan
Guang-Zhi
GZ
Peng
Zong-Gen
ZG
Zhu
Jian-Hua
JH
Meng
Shuai
S
Zhang
Tian
T
Gao
Lin-Yan
LY
Tao
Pei-Zhen
PZ
Gao
Rong-Mei
RM
Li
Yu-Huan
YH
Jiang
Jian-Dong
JD
Li
Zhuo-Rong
ZR
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004372:Ducks; D029822:Enterovirus B, Human / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D018347:Hepadnaviridae Infections / Q000188:drug therapy / Q000821:virology; D015611:Hepatitis B Virus, Duck / Q000187:drug effects / Q000502:physiology; D006518:Hepatitis Viruses / Q000187:drug effects*; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin