Hsp90 As A Target For Cellular Mechanisms Of Antiviral Drug Synthesis And Screening

The ansamycin antibiotic geldanamycin, first isolated from Streptomyces hygroscopicus, inhibits different viruses in vitro. It binds to Hsp90 chaperone protein, inactivates Hsp90 and inhibits the replication of virus. Having unique antiviral mechanism, geldanamycin shows broad-spectrum antiviral spectrum, low drug resistance and no cross resistance with other antiviral drugs. However it's difficult to develop systemic administration due to low water solubility, no selective distribution and high hepatotoxicity. In order to find new antiviral drugs, 11 derivatives of geldanamycin were synthesized and verified by MS and ~1HNMR.The cytotoxicities of all compounds were evaluated in MT-4,CEM and HEL cell. All compounds, except compound 7, 8 and 9, showed less toxicities than geldanamycin.The anti-HSV-1 and HSV-2 activities of 11 compounds were studied in VERO cell. All compounds showed higher inhibition activities than positive control acyclovir. The anti-HSV-1 activities of compound 3, 4, 7 and anti-HSV-2 activities of compound 3, 4, 5, 6 and 7 were similar to geldanamycin. Compound 3, 4, 5 and 6 showed better selective index(SI). Compound 3 and 4 deserve further research for their higher SI than geldanamycin.The activities of 3 and 4 against HSV-1 and HSV-2 were studied in mice through intragastric administration or peritoneal injection, by testing the mouse sera in VERO by MTT. In intragastric administration group, 3 showed higher activities against HSV-1 and HSV-2 than geldanamycin and positive control acyclovir. 4 showed lower anti-HSV-1 activities but higher anti-HSV-2 activities than acyclovir and geldanamycin. In peritoneal injection group, both 3 and 4 showed lower activities against HSV-1 and HSV-2 than acyclovir and geldanamycin. The blood drug level of compound 3 was high after intragastric administration, which means 3 having good oral availability and deserving further development. The anti-HIV-1 activities of 11 compounds were evaluated in MT-4 cell. All compounds, except 2, 8 and 9, showed good anti-HIV-1 activities in vitro. 7 had higher SI and anti-HIV-1 activity than geldanamycin. 4 showed significantly higher SI than leading compound with similar activity. The anti-HIV-1 activities of compound 1, 3, 4, 7 and 19 deserve further evaluation.In vitro evaluation of inhibition on HIV-1 enzyme showed that geldanamycin and its 11 derivatives were inactive on integrase, reverse transcriptase and protease, three key enzymes of HIV-1 replication. This verified that geldanamycin and its derivatives acted on different targets compared with other anti-HIV drugs used in clinical.In conclution, our results demonstrate that some derivatives of geldanamycin have similar anti-viral activities, better stabilities and lower toxicities compared with leading compound geldanamycin.