title: Inhibition of HIV-1 by curcumin A, a novel curcumin analog.
abstract: Despite the remarkable success of combination antiretroviral therapy at curtailing HIV progression, emergence of drug-resistant viruses, chronic low-grade inflammation, and adverse effects of combination antiretroviral therapy treatments, including metabolic disorders collectively present the impetus for development of newer and safer antiretroviral drugs. Curcumin, a phytochemical compound, was previously reported to have some in vitro anti-HIV and anti-inflammatory activities, but poor bioavailability has limited its clinical utility. To circumvent the bioavailability problem, we derivatized curcumin to sustain retro-aldol decomposition at physiological pH. The lead compound derived, curcumin A, showed increased stability, especially in murine serum where it was stable for up to 25 hours, as compared to curcumin that only had a half-life of 10 hours. Both curcumin and curcumin A showed similar inhibition of one round of HIV-1 infection in cultured lymphoblastoid (also called CEM) T cells (IC50=0.7 μM). But in primary peripheral blood mononuclear cells, curcumin A inhibited HIV-1 more potently (IC50=2 μM) compared to curcumin (IC50=12 μM). Analysis of specific steps of HIV-1 replication showed that curcumin A inhibited HIV-1 reverse transcription, but had no effect on HIV-1 long terminal repeat basal or Tat-induced transcription, or NF-κB-driven transcription at low concentrations that affected reverse transcription. Finally, we showed curcumin A induced expression of HO-1 and decreased cell cycle progression of T cells. Our findings thus indicate that altering the core structure of curcumin could yield more stable compounds with potent antiretroviral and anti-inflammatory activities.
authors.affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA ; Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Kumari
authors.affiliation: College of Pharmacy, Howard University, Washington, DC, USA.
authors.forename: Amol A
authors.initials: AA
authors.lastname: Kulkarni
authors.affiliation: Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Xionghao
authors.initials: X
authors.lastname: Lin
authors.affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA.
authors.forename: Charlee
authors.initials: C
authors.lastname: McLean
authors.affiliation: Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ammosova
authors.affiliation: Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hipolito
authors.affiliation: Department of Medicine, Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
authors.affiliation: Translational Neuroscience Laboratory, Howard University, Washington, DC, USA.
authors.forename: Evaristus
authors.initials: E
authors.lastname: Nwulia
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004790:Enzyme Induction; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D006207:Half-Life; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D003474:Curcumin
keywords: HIV-1; curcumin A; heme oxygenase-1; reverse transcription