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1.
J Dairy Sci ; 105(4): 2791-2802, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1699602

ABSTRACT

Bovine lactoferrin (bLF), a naturally occurring glycoprotein found in milk, has bioactive characteristics against many microbes, viruses, and other pathogens. Bovine lactoferrin strongly inhibits SARS-CoV-2 infection in vitro through direct entry inhibition and immunomodulatory mechanisms. This study reports on the anti-SARS-CoV-2 efficacy of commercially available bLF and common dairy ingredients in the human lung cell line H1437 using a custom high-content imaging and analysis pipeline. We also show for the first time that bLF has potent efficacy across different viral strains including the South African B.1.351, UK B.1.1.7, Brazilian P.1, and Indian Delta variants. Interestingly, we show that bLF is most potent against the B.1.1.7 variant [half-maximal inhibitory concentration (IC50) = 3.7 µg/mL], suggesting that this strain relies on entry mechanisms that are strongly inhibited by bLF. We also show that one of the major proteolysis products of bLF, lactoferricin B 17-41, has a modest anti-SARS-CoV-2 activity that could add to the clinical significance of this protein for SARS-CoV-2 treatment as lactoferricin is released by pepsin during digestion. Finally, we show that custom chewable lactoferrin tablets formulated in dextrose or sorbitol have equivalent potency to unformulated samples and provide an option for future human clinical trials. Lactoferrin's broad inhibition of SARS-CoV-2 variants in conjunction with the low cost and ease of production make this an exciting clinical candidate for treatment or prevention of SARS-CoV-2 in the future.


Subject(s)
COVID-19 , Lactoferrin , Animals , COVID-19/veterinary , Humans , Lactoferrin/pharmacology , Milk , SARS-CoV-2
2.
Nutrients ; 13(2)2021 Jan 23.
Article in English | MEDLINE | ID: covidwho-1575478

ABSTRACT

SARS-CoV-2 is a newly emerging virus that currently lacks curative treatments. Lactoferrin (LF) is a naturally occurring non-toxic glycoprotein with broad-spectrum antiviral, immunomodulatory and anti-inflammatory effects. In this study, we assessed the potential of LF in the prevention of SARS-CoV-2 infection in vitro. Antiviral immune response gene expression was analyzed by qRT-PCR in uninfected Caco-2 intestinal epithelial cells treated with LF. An infection assay for SARS-CoV-2 was performed in Caco-2 cells treated or not with LF. SARS-CoV-2 titer was determined by qRT-PCR, plaque assay and immunostaining. Inflammatory and anti-inflammatory cytokine production was determined by qRT-PCR. LF significantly induced the expression of IFNA1, IFNB1, TLR3, TLR7, IRF3, IRF7 and MAVS genes. Furthermore, LF partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells. Our in vitro data support LF as an immune modulator of the antiviral immune response with moderate effects against SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 , Gene Expression Regulation , Immunity, Innate/drug effects , Lactoferrin/pharmacology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , Caco-2 Cells , Chlorocebus aethiops , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Vero Cells
3.
Int J Mol Sci ; 22(20)2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1480796

ABSTRACT

Lactoferrins are an iron-binding glycoprotein that have important protective roles in the mammalian body through their numerous functions, which include antimicrobial, antitumor, anti-inflammatory, immunomodulatory, and antioxidant activities. Among these, their antimicrobial activity has been the most studied, although the mechanism behind antimicrobial activities remains to be elucidated. Thirty years ago, the first lactoferrin-derived peptide was isolated and showed higher antimicrobial activity than the native lactoferrin lactoferricin. Since then, numerous studies have investigated the antimicrobial potencies of lactoferrins, lactoferricins, and other lactoferrin-derived peptides to better understand their antimicrobial activities at the molecular level. This review defines the current antibacterial, antiviral, antifungal, and antiparasitic activities of lactoferrins, lactoferricins, and lactoferrin-derived peptides. The primary focus is on their different mechanisms of activity against bacteria, viruses, fungi, and parasites. The role of their structure, amino-acid composition, conformation, charge, hydrophobicity, and other factors that affect their mechanisms of antimicrobial activity are also reviewed.


Subject(s)
Anti-Infective Agents/pharmacology , Lactoferrin/pharmacology , Peptides/pharmacology , Animals , Anti-Infective Agents/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Lactoferrin/chemistry , Molecular Structure , Structure-Activity Relationship
4.
Acta Pharmacol Sin ; 42(11): 1913-1920, 2021 11.
Article in English | MEDLINE | ID: covidwho-1437673

ABSTRACT

Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.


Subject(s)
COVID-19 , Colitis, Ulcerative , Disulfiram/pharmacokinetics , Lactoferrin , Systemic Inflammatory Response Syndrome , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Biomimetic Materials/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Disease Models, Animal , Disulfiram/pharmacology , Drug Carriers/pharmacology , Humans , Immunosuppressive Agents/pharmacology , Lactoferrin/metabolism , Lactoferrin/pharmacology , Lipopolysaccharides/immunology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Nanoparticles/therapeutic use , Pyroptosis/drug effects , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , Treatment Outcome
5.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1366851

ABSTRACT

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Immunologic Factors/pharmacology , Lactoferrin/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , COVID-19/drug therapy , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Caco-2 Cells , Cell Line, Tumor , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Discovery , Drug Repositioning/methods , Epithelial Cells , Heparitin Sulfate/antagonists & inhibitors , Heparitin Sulfate/immunology , Heparitin Sulfate/metabolism , Hepatocytes , High-Throughput Screening Assays , Humans , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , Vero Cells
6.
Gut Microbes ; 13(1): 1961970, 2021.
Article in English | MEDLINE | ID: covidwho-1348030

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the ongoing global pandemic of coronavirus disease 2019 (COVID-19), which primarily manifests with respiratory distress and may also lead to symptoms associated with the gastrointestinal tract. Probiotics are living microorganisms that have been shown to confer immune benefits. In this study, we investigated the immunomodulatory effects and anti-SARS-CoV-2 activity of three different Lacticaseibacillus probiotic strains, either alone or in combination with lactoferrin, using the intestinal epithelial Caco-2 cell line. Our results revealed that the Lacticaseibacillus paracasei DG strain significantly induced the expression of genes involved in protective antiviral immunity and prevented the expression of proinflammatory genes triggered by SARS-CoV-2 infection. Moreover, L. paracasei DG significantly inhibited SARS-CoV-2 infection in vitro. L. paracasei DG also positively affected the antiviral immune activity of lactoferrin and significantly augmented its anti-SARS-CoV-2 activity in Caco-2 intestinal epithelial cells. Overall, our work shows that the probiotic strain L. paracasei DG is a promising candidate that exhibits prophylactic potential against SARS-CoV-2 infection.


Subject(s)
COVID-19/prevention & control , Lactobacillus/physiology , Lactoferrin/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Caco-2 Cells , Humans , Pandemics/prevention & control
7.
Eur Rev Med Pharmacol Sci ; 25(11): 4174-4184, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1281023

ABSTRACT

Currently, the COVID-19 pandemic, caused by the novel SARS-CoV-2 coronavirus, represents the greatest global health threat. Most people infected by the virus present mild to moderate respiratory symptoms and recover with supportive treatments. However, certain susceptible hosts develop an acute respiratory distress syndrome (ARDS), associated with an inflammatory "cytokine storm", leading to lung damage. Despite the current availability of different COVID-19 vaccines, the new emerging SARS-CoV-2 genetic variants represent a major concern worldwide, due to their increased transmissibility and rapid spread. Indeed, it seems that some mutations or combinations of mutations might confer selective advantages to the virus, such as the ability to evade the host immune responses elicited by COVID-19 vaccines. Several therapeutic approaches have been investigated but, to date, a unique and fully effective therapeutic protocol has not yet been achieved. In addition, steroid-based therapies, aimed to reduce inflammation in patients with severe COVID-19 disease, may increase the risk of opportunistic infections, increasing the hospitalization time and mortality rate of these patients. Hence, there is an unmet need to develop more effective therapeutic options. Here, we discuss the potential use of natural immunomodulators such as Thymosin α1 (Tα1), all-trans retinoic acid (ATRA), and lactoferrin (LF), as adjunctive or preventive treatment of severe COVID-19 disease. These agents are considered to be multifunctional molecules because of their ability to enhance antiviral host immunity and restore the immune balance, depending on the host immune status. Furthermore, they are able to exert a broad-spectrum antimicrobial activity by means of direct interactions with cellular or molecular targets of pathogens or indirectly by increasing the host immune response. Thus, due to the aforementioned properties, these agents might have a great potential in a clinical setting, not only to counteract SARS-CoV-2 infection, but also to prevent opportunistic infections in critically ill COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/immunology , Immunologic Factors/immunology , Immunologic Factors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Immunologic Factors/pharmacology , Lactoferrin/immunology , Lactoferrin/pharmacology , Lactoferrin/therapeutic use , Tretinoin/immunology , Tretinoin/pharmacology , Tretinoin/therapeutic use
8.
Int J Mol Sci ; 22(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1256562

ABSTRACT

A pandemic of acute respiratory infections, due to a new type of coronavirus, can cause Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) and has created the need for a better understanding of the clinical, epidemiological, and pathological features of COVID-19, especially in high-risk groups, such as pregnant women. Viral infections in pregnant women may have a much more severe course, and result in an increase in the rate of complications, including spontaneous abortion, stillbirth, and premature birth-which may cause long-term consequences in the offspring. In this review, we focus on the mother-fetal-placenta interface and its role in the potential transmission of SARS-CoV-2, including expression of viral receptors and proteases, placental pathology, and the presence of the virus in neonatal tissues and fluids. This review summarizes the current knowledge on the anti-viral activity of lactoferrin during viral infection in pregnant women, analyzes its role in the pathogenicity of pandemic virus particles, and describes the potential evidence for placental blocking/limiting of the transmission of the virus.


Subject(s)
Anti-Infective Agents/pharmacology , COVID-19/immunology , Infectious Disease Transmission, Vertical/prevention & control , Lactoferrin/pharmacology , Placenta/immunology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/immunology , COVID-19/complications , Female , Humans , Infant, Newborn , Lactoferrin/metabolism , Placenta/pathology , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/immunology
9.
Emerg Microbes Infect ; 10(1): 317-330, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1075417

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that lacks effective therapeutic interventions. SARS-CoV-2 infects ACE2-expressing cells and gains cell entry through either direct plasma membrane fusion or endocytosis. Recent studies have shown that in addition to ACE2, heparan sulfate proteoglycans (HSPGs) also play an important role in SARS-CoV-2 cell attachment by serving as an attachment factor. Binding of viral spike protein to HSPGs leads to the enrichment of local concentration for the subsequent specific binding with ACE2. We therefore hypothesize that blocking the interactions between viral spike protein and the HSPGs will lead to inhibition of viral replication. In this study, we report our findings of the broad-spectrum antiviral activity and the mechanism of action of lactoferrin (LF) against multiple common human coronaviruses as well as SARS-CoV-2. Our study has shown that LF has broad-spectrum antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E in cell culture, and bovine lactoferrin (BLF) is more potent than human lactoferrin. Mechanistic studies revealed that BLF binds to HSPGs, thereby blocking viral attachment to the host cell. The antiviral activity of BLF can be antagonized by the HSPG mimetic heparin. Combination therapy experiment showed that the antiviral activity of LF is synergistic with remdesivir in cell culture. Molecular modelling suggests that the N-terminal positively charged region in BLF (residues 17-41) confers the binding to HSPGs. Overall, LF appears to be a promising drug candidate for COVID-19 that warrants further investigation.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , Coronavirus/drug effects , Heparan Sulfate Proteoglycans/metabolism , Lactoferrin/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Cattle , Cell Line , Cells, Cultured , Drug Delivery Systems , Drug Synergism , Heparin/metabolism , Humans , Microbial Sensitivity Tests , Virus Attachment/drug effects
10.
Biomed Pharmacother ; 136: 111228, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1033016

ABSTRACT

Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.


Subject(s)
COVID-19/metabolism , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron/metabolism , Lactoferrin/therapeutic use , SARS-CoV-2 , Humans , Iron/blood , Iron/chemistry , Lactoferrin/pharmacology
11.
Eur J Pharmacol ; 885: 173499, 2020 Oct 15.
Article in English | MEDLINE | ID: covidwho-959755

ABSTRACT

The entry of SARS-CoV-2 into host cells proceeds by a proteolysis process, which involves the lysosomal peptidase cathepsin L. Inhibition of cathepsin L is therefore considered an effective method to decrease the virus internalization. Analysis from the perspective of structure-functionality elucidates that cathepsin L inhibitory proteins/peptides found in food share specific features: multiple disulfide crosslinks (buried in protein core), lack or low contents of (small) α-helices, and high surface hydrophobicity. Lactoferrin can inhibit cathepsin L, but not cathepsins B and H. This selective inhibition might be useful in fine targeting of cathepsin L. Molecular docking indicated that only the carboxyl-terminal lobe of lactoferrin interacts with cathepsin L and that the active site cleft of cathepsin L is heavily superposed by lactoferrin. A controlled proteolysis process might yield lactoferrin-derived peptides that strongly inhibit cathepsin L.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/physiology , Cathepsin L/antagonists & inhibitors , Food , Lactoferrin/pharmacology , Protease Inhibitors/pharmacology , Antiviral Agents/chemistry , Lactoferrin/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2 , Virus Internalization/drug effects
12.
Int J Mol Sci ; 21(14)2020 Jul 11.
Article in English | MEDLINE | ID: covidwho-646205

ABSTRACT

Recently, the world has been dealing with a devastating global pandemic coronavirus infection, with more than 12 million infected worldwide and over 300,000 deaths as of May 15th 2020, related to a novel coronavirus (2019-nCoV), characterized by a spherical morphology and identified through next-generation sequencing. Although the respiratory tract is the primary portal of entry of SARS-CoV-2, gastrointestinal involvement associated with nausea, vomiting and diarrhoea may also occur. No drug or vaccine has been approved due to the absence of evidence deriving from rigorous clinical trials. Increasing interest has been highlighted on the possible preventative role and adjunct treatment of lactoferrin, glycoprotein of human secretions part of a non-specific defensive system, known to play a crucial role against microbial and viral infections and exerting anti-inflammatory effects on different mucosal surfaces and able to regulate iron metabolism. In this review, analysing lactoferrin properties, we propose designing a clinical trial to evaluate and verify its effect using a dual combination treatment with local, solubilized intranasal spray formulation and oral administration. Lactoferrin could counteract the coronavirus infection and inflammation, acting either as natural barrier of both respiratory and intestinal mucosa or reverting the iron disorders related to the viral colonization.


Subject(s)
Coronavirus Infections/prevention & control , Lactoferrin/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Angiotensin-Converting Enzyme 2 , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Inflammation , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Iron/metabolism , Lactoferrin/pharmacology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2 , Virus Internalization/drug effects
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