HPLC-based purification and isolation of potent anti-HIV and latency reversing Daphnane Diterpenes from the medicinal plant Gnidia sericocephala (Thymelaeaceae)
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HPLC-based purification and isolation of potent anti-HIV and latency reversing Daphnane Diterpenes from the medicinal plant Gnidia sericocephala (Thymelaeaceae)
Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and
middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility.
Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to
HIV eradication. The “shock and kill” therapeutic approach aims to reactivate provirus expression in
latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An
attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting
viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is
used by traditional health practitioners in South Africa for HIV/AIDS management to supplement
cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part
of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV
latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC)
by >80% at 0.08 g/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal
effective concentration (EC50) of 0.03 M without cytotoxicity. Both 1 and 2 also reverse HIV latency
in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the
control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed
donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G.
sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting
HIV cure efforts in resource-limited regions.
Description:
SUPPLEMENTARY MATERIAL : TABLE S1: Anti-HIV replication activity of the positive control efavirenz using the in vitro deCIPhR assay: TABLE S2: Anti-HIV replication activity of G. sericocephala root extracts using the in vitro deCIPhR assay: TABLE S3: Cytotoxicity of G. sericocephala root extracts using the in vitro deCIPhR assay; FIGURE S1: 1H NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3): FIGURE S2: 13C NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3): FIGURE S3: The DEBT NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3).