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Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Stability of curcumin A in serum, serum-free media, complete media, PBS, and PBS supplemented with 10% BSA.Notes: Degradation of curcumin and curcumin A at different time points spanning 24 hours incubation, in presence of mouse serum (A), RPMI cell culture medium (B), RPMI supplemented with 10% fetal bovine serum (C), in PBS (D), and in PBS supplemented with 10% BSA (E).Abbreviations: PBS, phosphate-buffered saline; BSA, bovine serum albumin; RPMI, Roswell Park Memorial Institute.
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f2-dddt-9-5051: Stability of curcumin A in serum, serum-free media, complete media, PBS, and PBS supplemented with 10% BSA.Notes: Degradation of curcumin and curcumin A at different time points spanning 24 hours incubation, in presence of mouse serum (A), RPMI cell culture medium (B), RPMI supplemented with 10% fetal bovine serum (C), in PBS (D), and in PBS supplemented with 10% BSA (E).Abbreviations: PBS, phosphate-buffered saline; BSA, bovine serum albumin; RPMI, Roswell Park Memorial Institute.

Mentions: To analyze stability of curcumin A and compare it to curcumin, the compounds were incubated with mouse plasma, in complete or minimal cell culture media, and in PBS. The compounds were extracted from the incubation mixtures and resolved by nano-LC-MS mass spectrometry as described in Materials and methods. While curcumin had a half-life of 10 hours in mouse serum, curcumin A was stable for up to 24 hours of incubation (Figure 2A). In serum-free media, both curcumin and curcumin A were degraded, but curcumin A had a longer half-life (about 3 hours) compared to curcumin (about 1 hour) (Figure 2B). In complete media, curcumin and curcumin A were equally and relatively stable (Figure 2C). Incubation in PBS again showed increased stability of curcumin A (Figure 2D). To test whether BSA has a stabilizing effect on curcumin, curcumin and curcumin A were incubated in PBS supplemented with 10% BSA (Figure 2E). No stabilization and even a slight increase in degradation of curcumin was observed suggesting that BSA has no stabilizing effect on curcumin (Figure 2E). Taken together, curcumin A has improved stability and longer half-life, in serum, serum-free media, and PBS.


Inhibition of HIV-1 by curcumin A, a novel curcumin analog.

Kumari N, Kulkarni AA, Lin X, McLean C, Ammosova T, Ivanov A, Hipolito M, Nekhai S, Nwulia E - Drug Des Devel Ther (2015)

Stability of curcumin A in serum, serum-free media, complete media, PBS, and PBS supplemented with 10% BSA.Notes: Degradation of curcumin and curcumin A at different time points spanning 24 hours incubation, in presence of mouse serum (A), RPMI cell culture medium (B), RPMI supplemented with 10% fetal bovine serum (C), in PBS (D), and in PBS supplemented with 10% BSA (E).Abbreviations: PBS, phosphate-buffered saline; BSA, bovine serum albumin; RPMI, Roswell Park Memorial Institute.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562762&req=5

f2-dddt-9-5051: Stability of curcumin A in serum, serum-free media, complete media, PBS, and PBS supplemented with 10% BSA.Notes: Degradation of curcumin and curcumin A at different time points spanning 24 hours incubation, in presence of mouse serum (A), RPMI cell culture medium (B), RPMI supplemented with 10% fetal bovine serum (C), in PBS (D), and in PBS supplemented with 10% BSA (E).Abbreviations: PBS, phosphate-buffered saline; BSA, bovine serum albumin; RPMI, Roswell Park Memorial Institute.
Mentions: To analyze stability of curcumin A and compare it to curcumin, the compounds were incubated with mouse plasma, in complete or minimal cell culture media, and in PBS. The compounds were extracted from the incubation mixtures and resolved by nano-LC-MS mass spectrometry as described in Materials and methods. While curcumin had a half-life of 10 hours in mouse serum, curcumin A was stable for up to 24 hours of incubation (Figure 2A). In serum-free media, both curcumin and curcumin A were degraded, but curcumin A had a longer half-life (about 3 hours) compared to curcumin (about 1 hour) (Figure 2B). In complete media, curcumin and curcumin A were equally and relatively stable (Figure 2C). Incubation in PBS again showed increased stability of curcumin A (Figure 2D). To test whether BSA has a stabilizing effect on curcumin, curcumin and curcumin A were incubated in PBS supplemented with 10% BSA (Figure 2E). No stabilization and even a slight increase in degradation of curcumin was observed suggesting that BSA has no stabilizing effect on curcumin (Figure 2E). Taken together, curcumin A has improved stability and longer half-life, in serum, serum-free media, and PBS.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus