PMID: 

Sci Rep. 2017 09 6 ;7(1):10593. Epub 2017 Sep 6. PMID: 28878220

Abstract Title: 

Lactoferrin-derived Peptides Active towards Influenza: Identification of Three Potent Tetrapeptide Inhibitors.

Abstract: 

Bovine lactoferrin is a biglobular multifunctional iron binding glycoprotein that plays an important role in innate immunity against infections. We have previously demonstrated that selected peptides from bovine lactoferrin C-lobe are able to prevent both Influenza virus hemagglutination and cell infection. To deeper investigate the ability of lactoferrin derived peptides to inhibit Influenza virus infection, in this study we identified new bovine lactoferrin C-lobe derived sequences and corresponding synthetic peptides were synthesized and assayed to check their ability to prevent viral hemagglutination and infection. We identified three tetrapeptides endowed with broad anti-Influenza activity and able to inhibit viral infection in a concentration range femto- to picomolar. Our data indicate that these peptides may constitute a non-toxic tool for potential applications as anti-Influenza therapeutics.

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PMID: 

J Gastroenterol Hepatol. 2007 Nov ;22(11):1894-7. PMID: 17914966

Abstract Title: 

Effect of lactoferrin in patients with chronic hepatitis C: combination therapy with interferon and ribavirin.

Abstract: 

OBJECTIVES: Lactoferrin has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in patients with chronic hepatitis C (CHC). The aim of this study was to evaluate the effect of combined triple therapy of lactoferrin, interferon and ribavirin in patients with CHC.METHODS: A total of 111 Japanese patients with CHC were randomly assigned to a lactoferrin group (n = 50) and a control group (n = 61). The lactoferrin group was treated with lactoferrin for 8 weeks and then with lactoferrin, interferon and ribavirin for 24 weeks; the control group was treated with interferon and ribavirin for 24 weeks. Serum anti-lactoferrin antibody, clinical and laboratory measurement were determined.RESULTS: The mean HCV RNA titer significantly decreased at the end of lactoferrin monotherapy. Sustained virological response to therapy was significantly higher (P

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PMID: 

Hepatol Res. 2002 Nov ;24(3):228. PMID: 12393024

Abstract Title: 

Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes.

Abstract: 

We recently reported that lactoferrin (LF), a milk protein belonging to the iron transporter family, inhibits hepatitis C virus (HCV) infection in cultured human hepatocytes (PH5CH8) and that the interaction of LF with HCV is responsible for this inhibitory effect. As PH5CH8 cells were found to be a human hepatocyte line susceptible to hepatitis B virus (HBV) infection, we therefore examined if LF could effectively prevent HBV infection in PH5CH8 cells. Preincubation of the cell with bovine LF (bLF) or human LF (hLF) was required to prevent HBV infection of cells, and preincubation of HBV with bLF or hLF had no inhibitory effect on HBV infection. We further found that bovine transferrin, casein, and lactoalbumin had no anti-HBV activity. Our findings suggest that the interaction of LF with cells was important for its inhibitory effect, and that LF may well be among the candidates for an anti-HBV reagent that could prove effective in the treatment of patients with chronic hepatitis.

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PMID: 

Biochem Biophys Res Commun. 2013 May 17 ;434(4):791-6. Epub 2013 Apr 17. PMID: 23603257

Abstract Title: 

The protective effects of lactoferrin against murine norovirus infection through inhibition of both viral attachment and replication.

Abstract: 

The purpose of this study was to evaluate the effects of bovine lactoferrin against norovirus infection using mouse norovirus (MNV) and Raw264.7 cell in vitro. When Raw264.7 cells were infected with MNV in the presence or absence of lactoferrin, the cytotoxic damage to the infected Raw264.7 cells significantly and dose-dependently decreased and completely inhibited in the presence of 15 or 20μg/well of lactoferrin as compared with the absence of lactoferrin. Correspondingly, the MNV titers in the culture medium and intracellularly were significantly decreased in infected Raw264.7 cells treated with lactoferrin compared to control infected Raw264.7 cells. The mechanisms responsible forthe protective effects of lactoferrin against MNV infection were attributed to both its inhibition of the initial MNV attachment to cells and the subsequent interference with MNV replication. Moreover, it was revealed that lactoferrin could rapidly induce the expression of anti-viral cytokine mRNA,such as IFN-α and IFN-β which involved in inhibition of MNV replication in infected Raw264.7 cells, in the early phase of infection. It was concluded that lactoferrin exerts protective effects against MNV infection through inhibition of both viral attachment and replication. The present results provide evidence that lactoferrin may be useful as a preventive and/or therapeutic anti-norovirus agent.

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PMID: 

Antiviral Res. 2007 Dec ;76(3):252-62. Epub 2007 Aug 30. PMID: 17881064

Abstract Title: 

Bovine lactoferrin prevents the entry and intercellular spread of herpes simplex virus type 1 in Green Monkey Kidney cells.

Abstract: 

Lactoferrin (Lf) is a multifunctional glycoprotein that plays an important role in immune regulation and defence mechanisms against bacteria, fungi and viruses. Bovine lactoferrin (bLf) has been recognized as a potent inhibitor of human herpetic viruses, such as cytomegalovirus and herpes simplex virus type 1 and 2. BLf has been found to prevent viral infection by binding to heparan sulphate containing proteoglycans that also act as cell receptors for herpetic viruses. In this study we further investigated the inhibiting activity of bLf against herpes simplex virus type 1 (HSV-1) in Green Monkey Kidney (GMK) cells and found that, in addition to the viral adsorption step, bLf also targets the HSV-1 entry process and cell-to-cell viral spread. Our study showed that the inhibition of HSV-1 infectivity by bLf is dependent on its interaction with specific structural viral proteins. Apart from the prevention of early phases of viral infection, cell-to-cell spread inhibition activity of HSV-1 by bLf confirmed that this protein is an outstanding candidate for the treatment of herpetic infections since it would offer the advantage to prevent also viral infections caused by cell-associated virus.

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PMID: 

Antiviral Res. 1996 Mar ;29(2-3):221-31. PMID: 8739601

Abstract Title: 

Lactoferrin inhibits herpes simplex virus type 1 adsorption to Vero cells.

Abstract: 

This paper describes the ability of human and bovine lactoferrins (HLf; BLf), iron-binding proteins belonging to the non-immune defense system, to interfere with herpes simplex virus type 1 (HSV-1) infection. Since lactoferrins are known to bind to heparan sulphate proteoglycans and to low density lipoprotein receptor, which in turn act as binding sites for the initial interaction of HSV-1 with host cells, we tested the effect of these proteins on HSV-1 multiplication in Vero cells. Both HLf and BLf are found to be potent inhibitors of HSV-1 infection, the concentrations required to inhibit the vital cytopathic effect in Vero cells by 50% being 1.41 microM and 0.12 microM, respectively. HLf and BLf exerted their activity through the inhibition of adsorption of virions to the cells independently of their iron withholding property showing similar activity in the apo- and iron-saturated form. The binding of [35S]methionine-labelled HSV-1 particles to Vero cells was strongly inhibited when BLf was added during the attachment step. BLf interacts with both Vero cell surfaces and HSV-1 particles, suggesting that the hindrance of cellular receptors and/or of viral attachment proteins may be involved in its antiviral mechanism.

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PMID: 

J Enzyme Inhib Med Chem. 2016 ;31(1):23-30. Epub 2015 Feb 16. PMID: 25683083

Abstract Title: 

Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV.

Abstract: 

Two viral proteases of severe acute respiratory syndrome coronavirus (SARS-CoV), a chymotrypsin-like protease (3CL(pro)) and a papain-like protease (PL(pro)) are attractive targets for the development of anti-SARS drugs. In this study, nine alkylated chalcones (1-9) and four coumarins (10-13) were isolated from Angelica keiskei, and the inhibitory activities of these constituents against SARS-CoV proteases (3CL(pro) and PL(pro)) were determined (cell-free/based). Of the isolated alkylated chalcones, chalcone 6, containing the perhydroxyl group, exhibited the most potent 3CL(pro) and PL(pro) inhibitory activity with IC50 values of 11.4 and 1.2 µM. Our detailed protein-inhibitor mechanistic analysis of these species indicated that the chalcones exhibited competitive inhibition characteristics to the SARS-CoV 3CL(pro), whereas noncompetitive inhibition was observed with the SARS-CoV PL(pro).

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PMID: 

Transfusion. 2016 12 ;56(12):2948-2952. Epub 2016 Nov 2. PMID: 27805261

Abstract Title: 

Inactivation of Middle East respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment.

Abstract: 

BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) has been identified as a potential threat to the safety of blood products. The Mirasol Pathogen Reduction Technology System uses riboflavin and ultraviolet (UV) light to render blood-borne pathogens noninfectious while maintaining blood product quality. Here, we report on the efficacy of riboflavin and UV light against MERS-CoV when tested in human plasma.STUDY DESIGN AND METHODS: MERS-CoV (EMC strain) was used to inoculate plasma units that then underwent treatment with riboflavin and UV light. The infectious titers of MERS-CoV in the samples before and after treatment were determined by plaque assay on Vero cells. The treatments were initially performed in triplicate using pooled plasma (n = 3) and then repeated using individual plasma units (n = 6).RESULTS: In both studies, riboflavin and UV light reduced the infectious titer of MERS-CoV below the limit of detection. The mean log reductions in the viral titers were≥4.07 and ≥4.42 for the pooled and individual donor plasma, respectively.CONCLUSION: Riboflavin and UV light effectively reduced the titer of MERS-CoV in human plasma products to below the limit of detection, suggesting that the treatment process may reduce the risk of transfusion transmission of MERS-CoV.

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PMID: 

Antiviral Res. 2011 Apr ;90(1):64-9. Epub 2011 Feb 26. PMID: 21356245

Abstract Title: 

Emodin inhibits current through SARS-associated coronavirus 3a protein.

Abstract: 

The open-reading-frame 3a of SARS coronavirus (SARS-CoV) had been demonstrated previously to form a cation-selective channel that may become expressed in the infected cell and is then involved in virus release. Drugs that inhibit the ion channel formed by the 3a protein can be expected to inhibit virus release, and would be a source for the development of novel therapeutic agents. Here we demonstrate that emodin can inhibit the 3a ion channel of coronavirus SARS-CoV and HCoV-OC43 as well as virus release from HCoV-OC43 with a K1/2 value of about 20μM. We suggest that viral ion channels, in general, may be a good target for the development of antiviral agents.

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PMID: 

J Virol. 2004 Oct ;78(20):11334-9. PMID: 15452254

Abstract Title: 

Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells.

Abstract: 

Severe acute respiratory syndrome coronavirus (SARS-CoV) is the pathogen of SARS, which caused a global panic in 2003. We describe here the screening of Chinese herbal medicine-based, novel small molecules that bind avidly with the surface spike protein of SARS-CoV and thus can interfere with the entry of the virus to its host cells. We achieved this by using a two-step screening method consisting of frontal affinity chromatography-mass spectrometry coupled with a viral infection assay based on a human immunodeficiency virus (HIV)-luc/SARS pseudotyped virus. Two small molecules, tetra-O-galloyl-beta-D-glucose (TGG) and luteolin, were identified, whose anti-SARS-CoV activities were confirmed by using a wild-type SARS-CoV infection system. TGG exhibits prominent anti-SARS-CoV activity with a 50% effective concentration of 4.5 microM and a selective index of 240.0. The two-step screening method described here yielded several small molecules that can be used for developing new classes of anti-SARS-CoV drugs and is potentially useful for the high-throughput screening of drugs inhibiting the entry of HIV, hepatitis C virus, and other insidious viruses into their host cells.

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