The Antiviral Activity Of Geldanamycin And Anti-herpes Simplex Virus Type 1 Mechanism Of Action

Geldanamycin(GA) is an antibiotic with its primary target on theADP/ATP binding site of heat shock protein 90(Hsp90). In screening for antiviral candidates from the fermentation we found an active component against HSV-1. Chemical analysis of the purified compound showed a structure identical to that of GA.GA significantly inhinbited HSV-1 replication in Vero cells. IC50 of GA was 0.093 μ M and CC₅₀ of GA was 350 μ M, resulting in a therapeutic index of 3763. In animal experiments GA administration (0.093-0.37 mg/kg , ip or sc) one hour after HSV-1 infection (ip) protected the infected mice from death with survival rate of between 67 and 100% (ip), and 43.8% (sc), significantly higher than that of solvent controls (p<0.001 for ip injection and p<0.05 for sc injection). The acute LD₅₀ of GA in the mice was 15.5 mg/kg (ip).In a mouse HSV-2 vagina model, GA suspension administration to vagina after HSV-2 infection (1.43, 2.86 and 5.72 mg/kg, tid) protected the infected mice from death and increased average survival days in a dose-dependent manner, significantly higher than that of saline controls . The survival rates of 5.72mg/kg group was 100%, and 2.86mg/kg and 1.43mg/kg group were both 80%. The survival rates of all GA administration groups were highter than that of ACV control group. The average survival day were 14 days, 12.8 days and 12.7 days for the 5.72mg/kg group, 2.86mg/kg and 1.43mg/kg group respectively. The average survival day for all GA administration groups were longer that of ACV control group. GA also reduced HSV-2 sheding. After 48hrs post-infection, GA 5.72mg/kg, 2.86mg/kg and 1.43mg/kg groups reduced HSV-2 sheding by 794, 158 and 100 orders , as compared to saline controls. After 96hrs post-infection, GA 5.72mg/kg, 2.86mg/kg and...