Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors

• Published in: PloS one Vol. 10; no. 4; p. e0121099
• Main Authors: Tietjen, Ian, Ntie-Kang, Fidele, Mwimanzi, Philip, Onguéné, Pascal Amoa, Scull, Margaret A, Idowu, Thomas Oyebode, Ogundaini, Abiodun Oguntuga, Meva'a, Luc Mbaze, Abegaz, Berhanu M, Rice, Charles M, Andrae-Marobela, Kerstin, Brockman, Mark A, Brumme, Zabrina L, Fedida, David
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2015; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Anesthesiology; Antiretroviral agents; Aporphines - chemistry; Aporphines - pharmacology; Biological Products - chemistry; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - virology; Cell Line; Chemistry; Cytotoxicity; Drug resistance; Drug Resistance, Viral; Guanidines - pharmacology; Health sciences; Hepacivirus - drug effects; Hepacivirus - physiology; Hepatitis; Hepatitis C; Herbal medicine; HIV; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; Human Immunodeficiency Virus Proteins - antagonists & inhibitors; Human Immunodeficiency Virus Proteins - metabolism; Humans; Infectious diseases; Ion channels; Laboratories; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - virology; Lymphocytes; Lymphocytes T; Medical screening; Medicinal plants; Molecular Docking Simulation; Mutation; Natural products; Pan-Africanism; Pharmacy; Proanthocyanidins - chemistry; Proanthocyanidins - pharmacology; Protease; Protease inhibitors; Proteinase inhibitors; Proteins; Pyrazoles - pharmacology; Replication; Systematic review; Toxicity; Viral Regulatory and Accessory Proteins - antagonists & inhibitors; Viral Regulatory and Accessory Proteins - metabolism; Virology; Virus Replication - drug effects; Viruses; Canada; New York; Cameroon; United States > US; Africa; British Columbia Canada; Nigeria
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121099

The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world.