H84T BanLec has broad spectrum antiviral activity against human herpesviruses in cells, skin, and mice

Lloyd, Megan G; Liu, D; Legendre, Maureen; Markovitz, David M.; Moffat, Jennifer F.

doi:10.1038/s41598-022-05580-6

Cited by 12 publications

(9 citation statements)

References 54 publications

(88 reference statements)

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“…The mannose density of Man-emulsions is critical in cellular recognition and internalisation via a ManR-mediated mechanism [ 170 ]. A promising tool for investigating the glycosylation sites on the virion envelopes is H84T BanLec, a rationally produced dimer from the banana lectin that binds high-mannose N-glycans [ 176 ]. By binding to the glycosylated viral spike protein to prevent virus entrance into cells, BanLec demonstrates strong in vitro and in vivo action against human-pathogenic coronaviruses such as SARS-CoV-2, MERS-CoV, influenza, and human herpes viruses in cells, skin, and mice [ 176 – 178 ].…”

Section: Carbohydrate-directed Targeting (Glycotargeting)mentioning

confidence: 99%

Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine

Gupta

2022

J Nanopart Res

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Glycosylated nanoparticles (NPs) have drawn a lot of attention in the biomedical field over the past few decades, particularly in applications like targeted drug delivery. Mannosylated NPs and mannan-binding lectins/proteins (MBL/MBP) are emerging as promising tools for delivery of drugs, medicines, and enzymes to targeted tissues and cells as nanocarriers, enhancing their therapeutic benefits while avoiding the adverse effects of the drug. The occurrence of plenty of lectin receptors and their mannan ligands on cell surfaces makes them multifaceted carriers appropriate for specific delivery of bioactive drug materials to their targeted sites. Thus, the present review describes the tethering of mannose (Man) to several nanostructures, like micelles, liposomes, and other NPs, applicable for drug delivery systems. Bioadhesion through MBL-like receptors on cells has involvements applicable to additional arenas of science, for example gene delivery, tissue engineering, biomaterials, and nanotechnology. This review also focuses on the role of various aspects of drug/antigen delivery using (i) mannosylated NPs, (ii) mannosylated lectins, (iii) amphiphilic glycopolymer NPs, and (iv) natural mannan-containing polysaccharides, with most significant applications of MBL-based NPs as multivalent scaffolds, using different strategies. Graphical abstract Mannosylated NPs and/or MBL/MBP are coming up as viable and versatile tools as nanocarriers to deliver drugs and enzymes precisely to their target tissues or cells. The presence of abundant number of lectin receptors and their mannan ligands on cell surfaces makes them versatile carriers suitable for the targeted delivery of bioactive drugs.

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Section: Carbohydrate-directed Targeting (Glycotargeting)mentioning

confidence: 99%

Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine

Gupta

2022

J Nanopart Res

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“…Cellular toxicity was measured using a neutral red dye uptake assay, as previously described. ,, Briefly, ARPE-19 cells were seeded in tissue culture plates for 3 d. Cells were then treated for 72 h with a range of concentrations of the control and experimental compounds. Staurosporine, which causes apoptosis, served as the control for cell death.…”

Section: Resultsmentioning

confidence: 99%

“…ARPE-19 cells were seeded in 96-well tissue culture plates 3 d prior to infection and grown to confluence. Cells were infected with cell-free VZV-ORF57-Luc at an MOI of 0.01, as previously described. ,− At 2 h post-infection, the virus inoculum was removed, and the medium was replaced with controls or test compounds in 6 replicate wells. CDV or ACV (positive controls), or l -BHDU and its prodrugs, were incubated with infected cells for 72 h. Virus yield was determined by dividing the average total flux at each concentration by the average total flux of the untreated wells.…”

Section: Resultsmentioning

confidence: 99%

“…Antiviral activity against the VZV strains used here was evaluated in ARPE-19 cells as previously described. , Briefly, confluent ARPE-19 cells in a 96-well plate were infected with VZV at an approximate MOI of 0.01 for 2 h. Virus inoculum was removed, then the infected cells were treated with l -BHDU, its prodrugs, or the control compounds, CDV or ACV, at a range of concentrations. Virus spread was measured by bioluminescence (Total Flux) after 72 h. VZV yield was calculated as the average total flux for each concentration divided by the average Total Flux of the untreated wells.…”

Section: Methodsmentioning

confidence: 99%

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Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV)

et al. 2023

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Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous L-BHDU prodrugs: amino acid esters (14−26), phosphoramidates (33−34), long-chain lipids (ODE-L-BHDU-MP, 38, and HDP-L-BHDU-MP, 39), and phosphate ester prodrugs (POM-L-BHDU-MP, 41, and POC-L-BHDU-MP, 47). The amino acid ester L-BHDU prodrugs (L-phenylalanine, 16, and L-valine, 17) had a potent antiviral activity with EC 50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-L-BHDU-MP and POC-L-BHDU-MP had a significant anti-VZV activity with EC 50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC 50 > 100 μM) was detected. Out of these prodrugs, ODE-L-BHDU-MP (38) and POM-L-BHDU-MP (41) were selected for further evaluation in future studies.

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“…Viruses that typically infect oral epithelial tissues include the herpesviruses: Herpes Simplex type 1 (HSV-1), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Kaposi's sarcomaassociated herpesvirus (KSHV) [100]. Antimicrobial peptides appear to mitigate infections by acting directly on herpes simplex type 1 [101][102][103][104], SARS-CoV-2 [105], and KSHV [48]. The AMP LL-37 appears to inhibit infection by KSHV [48], whereas α-defensin-derived peptide HD5 suppresses infection by CMV [106], and lactoferrin attenuates HSV-1 [107].…”

Section: Spectrum Of Amp Activity Across Microbial Kingdomsmentioning

confidence: 99%

Antimicrobial peptides: Defending the mucosal epithelial barrier

Johnstone

Herzberg

2022

Front. Oral. Health

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The recent epidemic caused by aerosolized SARS-CoV-2 virus illustrates the importance and vulnerability of the mucosal epithelial barrier against infection. Antimicrobial proteins and peptides (AMPs) are key to the epithelial barrier, providing immunity against microbes. In primitive life forms, AMPs protect the integument and the gut against pathogenic microbes. AMPs have also evolved in humans and other mammals to enhance newer, complex innate and adaptive immunity to favor the persistence of commensals over pathogenic microbes. The canonical AMPs are helictical peptides that form lethal pores in microbial membranes. In higher life forms, this type of AMP is exemplified by the defensin family of AMPs. In epithelial tissues, defensins, and calprotectin (complex of S100A8 and S100A9) have evolved to work cooperatively. The mechanisms of action differ. Unlike defensins, calprotectin sequesters essential trace metals from microbes, which inhibits growth. This review focuses on defensins and calprotectin as AMPs that appear to work cooperatively to fortify the epithelial barrier against infection. The antimicrobial spectrum is broad with overlap between the two AMPs. In mice, experimental models highlight the contribution of both AMPs to candidiasis as a fungal infection and periodontitis resulting from bacterial dysbiosis. These AMPs appear to contribute to innate immunity in humans, protecting the commensal microflora and restricting the emergence of pathobionts and pathogens. A striking example in human innate immunity is that elevated serum calprotectin protects against neonatal sepsis. Calprotectin is also remarkable because of functional differences when localized in epithelial and neutrophil cytoplasm or released into the extracellular environment. In the cytoplasm, calprotectin appears to protect against invasive pathogens. Extracellularly, calprotectin can engage pathogen-recognition receptors to activate innate immune and proinflammatory mechanisms. In inflamed epithelial and other tissue spaces, calprotectin, DNA, and histones are released from degranulated neutrophils to form insoluble antimicrobial barriers termed neutrophil extracellular traps. Hence, calprotectin and other AMPs use several strategies to provide microbial control and stimulate innate immunity.

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H84T BanLec has broad spectrum antiviral activity against human herpesviruses in cells, skin, and mice

Cited by 12 publications

References 54 publications

Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine

Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine

Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV)

Antimicrobial peptides: Defending the mucosal epithelial barrier

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