SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control

Naidu, Sreus A G; Clemens, Roger; Naidu, A. S.

doi:10.1080/19390211.2022.2075072

Cited by 20 publications

(50 citation statements)

References 355 publications

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“…Hence, LF and its derived bioactive peptides seem to hinder the cell entry of SARS-CoV-2 through various mechanisms. Additionally, LF appears to inhibit SARS-CoV-2 also at the post-cell entry stage, since it was reported that LF treatment led to e. g. enhancement of interferon responses ( 24 ), inhibition of viral replication ( 29 ), or maintenance of iron homeostasis ( 30 ). Whether the N-terminal region of LF shares some of these antiviral mechanisms with full-length LF, remains to be determined in future studies.…”

Section: Discussionmentioning

confidence: 99%

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin

et al. 2022

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In addition to vaccines, there is an urgent need for supplemental antiviral therapeutics to dampen the persistent COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The transmembrane protease serine 2 (TMPRSS2), that is responsible for proteolytic priming of the SARS-CoV-2 spike protein, appears as a rational therapeutic target. Accordingly, selective inhibitors of TMPRSS2 represent potential tools for prevention and treatment of COVID-19. Previously, we identified the human milk glycoprotein lactoferrin as a natural inhibitor of plasminogen conversion to plasmin, a serine protease homologous to TMPRSS2. Here, we tested whether lactoferrin and lactoferricin, a biologically active natural peptide produced by pepsin-mediated digestion of lactoferrin, together with synthetic peptides derived from lactoferrin, were able to block TMPRSS2 and SARS-CoV-2 infection. Particularly, we revealed that both lactoferricin and the N-terminal synthetic peptide pLF1 significantly inhibited: i) proteolytic activity of TMPRSS2 and plasmin, ii) proteolytic processing of the SARS-CoV-2 spike protein, and iii) SARS-CoV-2 infection of SARS-CoV-2-permissive cells. Thus, natural and synthetic peptides derived from lactoferrin represent feasible candidates for supporting prevention and treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin

et al. 2022

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“…In phase III, there is thromboembolism with erythrocyte dysfunction involved along with hemolysis/heme release, increased prothrombin time, and elevated D-dimers, which are cumulatively linked to severe coagulopathies and the multiorgan dysfunction syndrome . Thus, some scientists claim that COVID-19 should be classified as a “FeRD syndrome.” 44 …”

Section: Iron-redox Dysregulation and Csd In Covid-19/pascmentioning

confidence: 99%

“…Interestingly, many of these long haulers have no previous laboratory confirmation of COVID-19, which raises skepticism that the persistent PASC symptoms are an outcome of a different metabolic malfunction. The FeRD syndrome, along with viral-induced host metabolic reprogramming and altered host mitochondrial function (innate bioenergetics), may explain both virus(+ve)-COVID-19 and virus(−ve)-PASC pathologies, and research on this must continue 44 . Persistent CSD (loss of smell and taste) may lead to malnutrition and hypoenergetic (low-ATP) metabolic state, with the development of sarcopenia (involuntary muscle loss/weakness) and chronic fatigue syndrome in COVID-19 survivors and PASC patients 75 .…”

Section: Perspectives For the Future And Conclusionmentioning

confidence: 99%

“…Therefore, nutritional restoration of host metabolic reprogramming and mitochondrial function may provide an effective strategy to reverse FeRD syndrome and combat CSD in COVID-19/PASC. Innate regulators of iron-redox homeostasis, such as LF, heme oxygenase-1, erythropoietin, and hepcidin modulators, 44 could serve as potential CSD rehabilitation interventions for OD/GD recovery. These iron-redox homeostasis regulators could also play a vital role in alleviating cellular oxidative stress and inflammation, particularly the CSD pathobiology in COVID-19/PASC.…”

Section: Perspectives For the Future And Conclusionmentioning

confidence: 99%

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No Smell, No Taste—Dealing With a “Senseless” Phase of the Pandemic

Naidu

Clemens

2022

Nutr Today

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The SARS-CoV-2 infection alters smell and taste sensations in many patients. These 2 neurosensory impairments, namely, (1) the loss of smell, an olfactory dysfunction (OD) or anosmia, and (2) the loss of taste, a gustatory dysfunction (GD) or ageusia, are often the earliest and, sometimes, the only signs in otherwise asymptomatic individuals. Both OD and GD are recognized by the international scientific community as one of the critical symptoms of COVID-19. The prevalence of COVID-19–related OD is higher among women (although less likely to experience severe forms of SARS-CoV-2 infection) than men. The total loss of taste sense or GD is more common among the elderly COVID-19 patients than in the younger population. In “long” COVID or postacute sequelae of COVID-19 (PASC) patients, OD/GD could persist for months to years, depending on the extent of damage caused by the SARS-CoV-2 infection to the olfactory and gustatory systems. Olfactory dysfunction and GD manifestations may severely disrupt quality of life, which includes altered eating habits, loss of appetite, weight change, and loss of pleasure in food consumption, and may further affect psychological well-being, social bonding, altered intimacy, and relationship to self and others. The hedonic value of diet relies exclusively on its flavor; however, the onset of OD/GD during SARS-CoV-2 infection deprives such organoleptic experiences of nutrition. To compensate for these OD/GD issues, the chemosensory focus of COVID-19/PASC patients during dietary consumption may shift toward food texture (to stimulate trigeminal nerves) and food colors (to stimulate brain activity), to sustain appetite as well as enhance the pleasure of eating. Olfactory training with repeated exposure to 4 intense odors twice daily has been a traditional rehabilitation practice to alleviate olfactory impairments in COVID-19. The neurosensory impairments in COVID-19 pathobiology culminate from iron-redox dysregulation, viral-induced host metabolic reprogramming, and host mitochondrial dysfunction. Therefore, nutritional restoration of host metabolic reprogramming and mitochondrial function could provide an effective strategy to reverse iron-redox dysregulation syndrome and combat OD/GD in COVID-19 and PASC patients. Innate regulators of iron-redox homeostasis, such as lactoferrin, heme oxygenase-1, erythropoietin, and hepcidin modulators, could serve as potential interventions for OD/GD recovery.

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“…The studies on the design of SARS-CoV-2 antivirals are complicated by the presence of multiple receptors on a host cell surface that the virus uses to enter the cell, such as angiotensin-converting enzyme 2 (ACE2), neuropilin-1, CD147, tyrosine-protein kinase receptor UFO (AXL) and other co-receptors (Scialo et al 2020 ; Shang et al 2020 ; Zhang et al 2020 ; Wang et al 2020a , 2021 ; Wei et al 2020 ; Daly et al 2020 ; Cantuti-Castelvetri et al 2020 ; Jackson et al 2022 ). Dysregulation of iron metabolism in SARS-CoV-2-infected patients, which is associated with onset of hypoxia, inflammation, and the response to oxidative stress has been widely reviewed (Cavezzi et al 2022 ; Naidu et al 2022 ; Kronstein-Wiedemann et al 2022 ; Suriawinata and Mehta 2022 ). In this regard, the therapeutic potential of lactoferrin (Lf), a cationic homologue of serum transferrin (Tf), has been widely discussed as a regulator of inflammation, iron metabolism, tolerance to hypoxia and oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Molecular mimicry of the receptor-binding domain of the SARS-CoV-2 spike protein: from the interaction of spike-specific antibodies with transferrin and lactoferrin to the antiviral effects of human recombinant lactoferrin

et al. 2022

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The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves dysregulations of iron metabolism, and although the mechanism of this pathology is not yet fully understood, correction of iron metabolism pathways seems a promising pharmacological target. The previously observed effect of inhibiting SARS-CoV-2 infection by ferristatin II, an inducer of transferrin receptor 1 (TfR1) degradation, prompted the study of competition between Spike protein and TfR1 ligands, especially lactoferrin (Lf) and transferrin (Tf). We hypothesized molecular mimicry of Spike protein as cross-reactivity of Spike-specific antibodies with Tf and Lf. Thus, strong positive correlations (R 2 > 0.95) were found between the level of Spike-specific IgG antibodies present in serum samples of COVID-19-recovered and Sputnik V-vaccinated individuals and their Tf-binding activity assayed with peroxidase-labeled anti-Tf. In addition, we observed cross-reactivity of Lf-specific murine monoclonal antibody (mAb) towards the SARS-CoV-2 Spike protein. On the other hand, the interaction of mAbs produced to the receptor-binding domain (RBD) of the Spike protein with recombinant RBD protein was disrupted by Tf, Lf, soluble TfR1, anti-TfR1 aptamer, as well as by peptides RGD and GHAIYPRH. Furthermore, direct interaction of RBD protein with Lf, but not Tf, was observed, with affinity of binding estimated by K D to be 23 nM and 16 nM for apo-Lf and holo-Lf, respectively. Treatment of Vero E6 cells with apo-Lf and holo-Lf (1–4 mg/mL) significantly inhibited SARS-CoV-2 replication of both Wuhan and Delta lineages. Protective effects of Lf on different arms of SARS-CoV-2-induced pathogenesis and possible consequences of cross-reactivity of Spike-specific antibodies are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s10534-022-00458-6.

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SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control

Cited by 20 publications

References 355 publications

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin

No Smell, No Taste—Dealing With a “Senseless” Phase of the Pandemic

Molecular mimicry of the receptor-binding domain of the SARS-CoV-2 spike protein: from the interaction of spike-specific antibodies with transferrin and lactoferrin to the antiviral effects of human recombinant lactoferrin

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