Prenylated phloroglucinols from Hypericum scruglii, an endemic species of Sardinia (Italy), as new dual HIV-1 inhibitors effective on HIV-1 replication

Abstract

In a search for new potential multitarget anti-HIV compounds from natural products, we have identified in Hypericum scruglii, an endemic and exclusive species of Sardinia (Italy), a potent plant lead. The phytochemical study of the hydroalcoholic extract obtained from its leaves led to the isolation of its most abundant secondary metabolites, belonging to different chemical classes. In particular, three phloroglucinols derivatives were identified, confirming their significance as chemotaxonomic markers of the Hypericum genus. Among them, the 3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl)phloroglucinol was reported here for the first time. All six isolated compounds have been evaluated firstly for the inhibition of both Human Immunodeficiency Virus type 1 (HIV-1) Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities, for the inhibition of HIV-1 integrase (IN) in biochemical assays, and also for their effect on viral replication. Among the isolated metabolites, three phloroglucinol derivatives and quercitrin were effective on both RT-associated RDDP and RNase H activities in biochemical assays. The same active compounds affected also HIV-1 IN strand transfer function, suggesting the involvement of the RNase H active site. Furthermore, phloroglucinols compounds, included the newly identified compound, were able to inhibit the HIV-1 replication in cell based assays.

So Uncommon and so Singular, but Underexplored: An Updated Overview on Ethnobotanical Uses, Biological Properties and Phytoconstituents of Sardinian Endemic Plants

“…In particular, betulinic acid, a triterpene compound already known for its antiviral activity [85], was also active on HIV-1 mutant RTs resistant to efavirenz [84]. Recently, the anti-HIV-1 activity of some phloroglucinol derivatives isolated from aerial parts of H. scruglii has been described [86]. In this case, a previously undescribed acylphloroglucinol was able to inhibit the virus replication.…”

“…Remarkably, bioprospecting of Sardinian endemic taxa has yielded, along with a high number of known compounds, one-hundred and four previously undescribed metabolites. Out of the new compounds, some are endowed with interesting biological properties [48,81,82,86,105,185]. In particular, the highest number of new metabolites has been detected from E. semiperfoliata, E. pithyusa ssp.…”

Ribonuclease H, an unexploited target for antiviral intervention against HIV and hepatitis B virus

“…Its effect on viral replication and eventual cytotoxicity were not determined. Most recently, Onopordum illyricum L. (Sanna et al, 2018a) and Hypericum scruglii (Sanna et al, 2018b) were also reported to be promising sources of anti-HIV-1 molecules. Among them, 1,5-dicaffeoylquinic acid from Onopordum Illyricum L. showed an interesting profile as dual inhibitor of RT-associated RNase H and IN strand transfer activities (IC 50 values of 16.9 µM and 0.5 µM, respectively), proving to be not cytotoxic at concentrations as high as 50 µM.…”

“…The analysis of the effect of components of Hypericum scruglii (Sanna et al, 2018b), revealed that three prenylated phloroglucinols (Figure 15), were able to inhibit HIV-1 replication with EC 50 values ranging from 3.5 to 8 μM and CC 50 values above 50 μM. All of them were able to inhibit the RT-associated RNase H in the low micromolar range.…”

Antitumor Potential and Phytochemical Profile of Plants from Sardinia (Italy), a Hotspot for Biodiversity in the Mediterranean Basin

“…Among them, 189 are exclusive to Sardinia, 90 are Sardinian-Corsican endemics, and 16 taxa are also present in the Tuscan Archipelago [6]. Even though scientific evidence confirmed their interesting phytochemical and biological features [7][8][9][10], to date most Sardinian endemic plants remained scantly or not at all investigated.…”