HPLC-Based Purification and Isolation of Potent Anti-HIV and Latency Reversing Daphnane Diterpenes from the Medicinal Plant <i>Gnidia sericocephala</i> (<i>Thymelaeaceae</i>)
Babalwa Tembeni,
Amanda Sciorillo,
Luke Invernizzi,
Thomas Klimkait,
Lorena Urda,
Phanankosi Moyo,
Dashnie Naidoo-Maharaj,
Nathan Levitties,
Kwasi Gyampoh,
Guorui Zu,
Zhe Yuan,
Karam Mounzer,
Siphathimandla Nkabinde,
Magugu Nkabinde,
Nceba Gqaleni,
Ian Tietjen,
Luis J. Montaner,
Vinesh Maharaj
Affiliations
Babalwa Tembeni
Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
Amanda Sciorillo
The Wistar Institute, Philadelphia, PA 19104, USA
Luke Invernizzi
Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
Thomas Klimkait
Molecular Virology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Lorena Urda
Molecular Virology, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Phanankosi Moyo
Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
Dashnie Naidoo-Maharaj
Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
Nathan Levitties
The Wistar Institute, Philadelphia, PA 19104, USA
Kwasi Gyampoh
The Wistar Institute, Philadelphia, PA 19104, USA
Guorui Zu
The Wistar Institute, Philadelphia, PA 19104, USA
Zhe Yuan
The Wistar Institute, Philadelphia, PA 19104, USA
Karam Mounzer
Jonathan Lax Immune Disorders Treatment Center, Philadelphia Fight Community Health Centers, Philadelphia, PA 19107, USA
Siphathimandla Nkabinde
Ungangezulu Indigenous Remedies, J Uitval, Wasbank 2920, South Africa
Magugu Nkabinde
Ungangezulu Indigenous Remedies, J Uitval, Wasbank 2920, South Africa
Nceba Gqaleni
Africa Health Research Institute, Congella 4013, South Africa
Ian Tietjen
The Wistar Institute, Philadelphia, PA 19104, USA
Luis J. Montaner
The Wistar Institute, Philadelphia, PA 19104, USA
Vinesh Maharaj
Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
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 µg/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 µM 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.
