Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Kumari, Namita; Iordanskiy, Sergey; Kovalskyy, Dmytro; Breuer, Denitra; Niu, Xiaomei; Lin, Xionghao; Xu, Min; Gavrilenko, Konstantin S.; Kashanchi, Fatah; Dhawan, Subhash; Nekhai, Sergeï

doi:10.1128/aac.02918-14

Cited by 15 publications

(14 citation statements)

References 58 publications

(79 reference statements)

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“…Treatment with ferric ammonium citrate further increased HIV-1 inhibition in SCD PBMCs but had no effect on HIV-1 infection in control PBMCs (Figure 2E, iron). Treatment with iron chelator, PPYeT, 25 inhibited HIV-1 replication in control PBMCs in accord with our previous study, 25 and further inhibited HIV-1 in SCD PBMCs (Figure 2E, chelator). These observations suggested that iron metabolism was altered in SCD PBMCs, and that iron depletion by an iron chelator or ferroportin inhibited HIV-1.…”

Section: Resultssupporting

confidence: 91%

“…Intracellular iron levels were then analyzed using calcein fluorescent sensor. 25 PBMCs were treated with nonfluorescent cell-permeable calcein AM, which is converted to calcein in the cells whose fluorescence is quenched upon binding to iron. A fractional fluorescence (F − F 0 )/F, which is inversely proportional to the amount of labile chelatable iron, was markedly higher in SCD PBMCs (Figure 3B), suggesting a reduced LIP in SCD PBMCs.…”

Section: Resultsmentioning

confidence: 99%

“…Iron chelators, on the other hand, inhibited HIV-1 infection in both SCD and normal controls in accord with our previous observations. 25–27 Remarkably, ferroportin expression in SCD PBMCs explains the long standing paradox of the near absence of HIV-1 infection in patients with SCD. Expression of ferroportin was shown to control intracellular bacterial pathogens, including Salmonella , Chlamydia , and Legionella .…”

Section: Discussionmentioning

confidence: 99%

“…25–27 We recently showed that iron chelators induce IKBα expression. 25 Because the HIV-1 promoter contains 2 NF-κB binding sites, 49 its activity is critically dependent on NF-κB. The NF-κB availability was shown to be increased by iron efflux that activates IκB kinase.…”

Section: Discussionmentioning

confidence: 99%

“…24 Depletion of intracellular iron inhibits CDK2 activity and blocks HIV-1 transcription. 25–27 Iron chelators have been shown to induce the expression of p21, 28,29 which can inhibit CDK2. 30 Physiologically, cellular iron is exported by an iron export protein, ferroportin, which is negatively regulated by hepcidin.…”

Section: Introductionmentioning

confidence: 99%

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Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Kumari¹,

Ammosova²,

Diaz³

et al. 2016

Blood Advances

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The low incidence of HIV-1 infection in patients with sickle cell disease (SCD) and inhibition of HIV-1 replication in vitro under the conditions of low intracellular iron or heme treatment suggests a potential restriction of HIV-1 infection in SCD. We investigated HIV-1 ex vivo infection of SCD peripheral blood mononuclear cells (PBMCs) and found that HIV-1 replication was inhibited at the level of reverse transcription (RT) and transcription. We observed increased expression of heme and iron-regulated genes, previously shown to inhibit HIV-1, including ferroportin, IKBα, HO-1, p21, and SAM domain and HD domain-containing protein 1 (SAMHD1). HIV-1 inhibition was less pronounced in hepcidin-treated SCD PBMCs and more pronounced in the iron or iron chelators treated, suggesting a key role of iron metabolism. In SCD PBMCs, labile iron levels were reduced and protein levels of ferroportin, HIF-1α, IKBα, and HO-1 were increased. Hemin treatment induced ferroportin expression and inhibited HIV-1 in THP-1 cells, mimicking the HIV-1 inhibition in SCD PBMCs, especially as hepcidin similarly prevented HIV-1 inhibition. In THP-1 cells with knocked down ferroportin, IKBα, or HO-1 genes but not HIF-1α or p21, HIV-1 was not inhibited by hemin. Activity of SAMHD1-regulatory CDK2 was decreased, and SAMHD1 phosphorylation was reduced in SCD PBMCs and hemin-treated THP-1 cells, suggesting SAMHD1-mediated HIV-1 restriction in SCD. Our findings point to ferroportin as a trigger of HIV-1 restriction in SCD settings, linking reduced intracellular iron levels to the inhibition of CDK2 activity, reduction of SAMHD1 phosphorylation, increased IKBα expression, and inhibition of HIV-1 RT and transcription.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Kumari¹,

Ammosova²,

Diaz³

et al. 2016

Blood Advances

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Design of Tat-Activated Cdk9 Inhibitor

Zhao

Chen

et al. 2018

Int J Pept Res Ther

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Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

Liu

Zhang

Nekhai

et al. 2020

Curr Clin Micro Rpt

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140

170

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Purpose of the review The ongoing outbreak of novel coronavirus pneumonia caused by the 2019 novel coronavirus (SARS-CoV-2) in China is lifting widespread concerns. Thus, therapeutic options are urgently needed, and will be discussed in this review. Recent findings Iron-containing enzymes are required for viruses most likely including coronaviruses (CoVs) to complete their replication process. Moreover, poor prognosis occurred in the conditions of iron overload for patients upon infections of viruses. Thus, limiting iron represents a promising adjuvant strategy in treating viral infection through oral uptake or venous injection of iron chelators, or through the manipulation of the key iron regulators. For example, treatment with iron chelator deferiprone has been shown to prolong the survival of acquired immunodeficiency syndrome (AIDS) patients. Increasing intracellular iron efflux via increasing iron exporter ferroportin expression also exhibits antiviral effect on human immunodeficiency virus (HIV). The implications of other metals besides iron are also briefly discussed. Summary For even though we know little about iron regulation in COVID-19 patients thus far, it could be deduced from other viral infections that iron chelation might be an alternative beneficial adjuvant in treating COVID-19.

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Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Cited by 15 publications

References 58 publications

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

Design of Tat-Activated Cdk9 Inhibitor

Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival

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