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.

Curcumin as an Antiviral Agent

“…Replication Human immunodeficiency virus [11] APE1 redox reactions Replication Kaposi's sarcoma-associated herpesvirus [12] Cell lipogenesis Replication Dengue virus [8]…”

Extracellular Vesicles from Human Papilloma Virus-Infected Cervical Cancer Cells Enhance HIV-1 Replication in Differentiated U1 Cell Line

“…Curcumin and cucurbitacin-D are shown to inhibit cancer growth in the cervix by inducing apoptosis and arresting the cell cycle [32,33]. In addition to their anti-cancer properties, curcumin and cucurbitacin also suppress HIV-1 pathogenesis through their antioxidant potential [34,35]. Curcumin is shown to reduce HIV-1 transcription by inhibiting the HIV-1 protein, Tat-mediated LTR promotor transactivation [34].…”

“…Chemodietary agents such as curcumin and cucurbitacin-D are known to reduce cancer progression [32,33], as well as HIV-1 replication [34,35], through their antioxidant potential. We treated curcumin (20 µM) and cucurbitacin-D (0.1 µM) to CCS or CCS-EVs-treated U1 cells for four days, every 24 h, with an assumption that they would combat the oxidative stress caused by CCS or CCS-EVs and hence reduce the viral replication in U1 cells.…”

In Search of Feasible Interventions for the Prevention and Cure of Novel Coronavirus Disease 2019<strong> </strong>

“…Various commercially available antiviral drugs have been shown to be effective against SARS-CoV [25] and SARS-CoV-2 [26]. Since the curcumin has also been proved as a promising natural compound against many viruses [27][28][29][30][31]…”

“…turmeric, and its active ingredient curcumin, which has previously been shown effective in inhibiting the virus replication in human cells due to its anti-viral activities as demonstrated for HIV and AIDS [27][28][29], Zika and chikungunya [30] and herpes simplex virus [31], may also be explored for its possible preventive and treatment option for the COVID-19 pandemic. The research efforts may be guided towards finding whether (i) Cucumin or turmeric inhibits SARS-CoV-2 replication in human cells as demonstrated for HIV and AIDS [27][28][29], Zika and chikungunya [30] and herpes simplex virus [31] (ii) whether cucumin or turmeric has a role in controlling the SARS-CoV-2 infection by inhibiting its entry into the host cell. It has also been shown that Zika and chikungunya virus incubated with curcumin loses its infectivity [30], this property of curcumin may also be explored for the possible inactivation of SARS-CoV-2.…”