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.

The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria. Urgent measures need to be taken to curb this impending challenge. The higher plant-derived sesquiterpene, quinoline alkaloids, and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed. Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed. The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P. falciparum. To identify these novel scaffolds, we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data. Natural products were assigned to different structural classes using NPClassifier. To identify the most promising chemical scaffolds, we then correlated natural compound class with bioactivity and other data, namely (i) potency, (ii) resistance index, (iii) selectivity index and (iv) physicochemical properties. We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data. From this analysis we identified the top-ranked natural product pathway as the alkaloids. The top three ranked super classes identified were (i) pseudoalkaloids, (ii) naphthalenes and (iii) tyrosine alkaloids and the top five ranked classes (i) quassinoids (of super class triterpenoids), (ii) steroidal alkaloids (of super class pseudoalkaloids) (iii) cycloeudesmane sesquiterpenoids (of super class triterpenoids) (iv) isoquinoline alkaloids (of super class tyrosine alkaloids) and (v) naphthoquinones (of super class naphthalenes). Launched chemical space of these identified classes of compounds was, by and large, distinct from that of ‘legacy’ antimalarial drugs. Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs. These molecules have the potential to be developed into new antimalarial drugs.