title: Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada; Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tietjen
authors.affiliation: Department of Chemistry, Chemical and Bioactivity Information Centre, Faculty of Science, University of Buea, Buea, Cameroon.
authors.forename: Fidele
authors.initials: F
authors.lastname: Ntie-Kang
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Mwimanzi
authors.affiliation: Department of Chemistry, Faculty of Science, University of Douala, Douala, Cameroon.
authors.forename: Pascal Amoa
authors.initials: PA
authors.lastname: Onguéné
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Scull
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Thomas Oyebode
authors.initials: TO
authors.lastname: Idowu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Abiodun Oguntuga
authors.initials: AO
authors.lastname: Ogundaini
authors.affiliation: Department of Chemistry, Faculty of Science, University of Douala, Douala, Cameroon.
authors.forename: Luc Mbaze
authors.initials: LM
authors.lastname: Meva'a
authors.affiliation: African Academy of Sciences, Nairobi, Kenya.
authors.forename: Berhanu M
authors.initials: BM
authors.lastname: Abegaz
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States of America.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Andrae-Marobela
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Fedida
mesh_terms: D001060:Aporphines / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D002460:Cell Line; D024882:Drug Resistance, Viral; D006146:Guanidines / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D054298:Human Immunodeficiency Virus Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D062105:Molecular Docking Simulation; D044945:Proanthocyanidins / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000086082:Viroporin Proteins
chemical_list: D001060:Aporphines; D001688:Biological Products; D006146:Guanidines; D054298:Human Immunodeficiency Virus Proteins; D044945:Proanthocyanidins; D011720:Pyrazoles; D054334:Viral Regulatory and Accessory Proteins; C570889:N-(5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl)guanidine; C555286:ixoratannin A-2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C011686:boldine
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