Hypericum hircinum L. components as new single molecule inhibitors of both HIV-1 reverse transcriptase-associated DNA polymerase and ribonuclease H activities.

Among HIV-1 Reverse Transcriptase (RT) associated functions, DNA polymerase and Ribonuclease H (RNase H) are both essential for HIV replication and excellent targets for drug development (1). While all RT inhibitors approved for therapy target the DNA polymerase activity, there is the pressing need for new RT inhibitors possibly targeting the RNase H function (2-4). In the last twenty years many natural substances have shown antiviral activity against HIV-1, but only a few against the RNase H function. We have tested the ethanolic extracts obtained by the Hypericum hircinum L. (Hypericaceae) growing in Sardinia (Italy) on the HIV-1 RT-associated RNase H function and found that they have inhibitory effects. Active extracts were fractionated up to obtain the main components which have been isolated, tested and identified to be betulinic acid, shikimic acid, chlorogenic acid, quercetin, 5,7,3’,5’- tetrahydroxyflavanone and 5,7,3’,5’-tetrahydroxyflavanone 7-O-glucoside. Betulinic acid and 5,7,3’,5’-tetrahydroxyflavanone 7-O-glucoside were active on both RT-associated activities and betulinic acid was also active on HIV-1 mutant RTs resistant to efavirenz. We have identify new chemical structures that may be used as anti-HIV-1 RNase H lead compound for drug further development, we have evaluated the H. hircinum L. ethanol extracts from its aerial part on the HIV-1 RT-associated RNase H activity and isolated the main active chemical constituents. Results show that components never reported for this plant are able to inhibit both HIV-1 RT associated functions and represent an interesting lead for new single molecule dual HIV inhibitors.