Receptor mimicry as novel therapeutic treatment for biothreat agents

doi:10.4161/bbug.1.1.10049

Cited by 24 publications

(11 citation statements)

References 153 publications

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“…Multimeric Fcs may nonetheless be useful, for example when delivering antigens in vaccines or as high avidity receptor blockers. Many pathogens rely on glycans to infect host cells ( 45 ), and differentially glycosylated Fc multimers may be useful inhibitors of infection. One immediate application for our hypersialylated molecules may be to block Siglec-1–dependent trans-infection of lymphocytes by retroviruses, including HIV and human T-cell leukemia viruses ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors

Blundell

Allen

et al. 2017

Journal of Biological Chemistry

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Multimeric fragment crystallizable (Fc) regions and Fc-fusion proteins are actively being explored as biomimetic replacements for IVIG therapy, which is deployed to manage many diseases and conditions but is expensive and not always efficient. The Fc region of human IgG1 (IgG1-Fc) can be engineered into multimeric structures (hexa-Fcs) that bind their cognate receptors with high avidity. The critical influence of the unique N-linked glycan attached at Asn-297 on the structure and function of IgG1-Fc is well documented; however, whether the N-linked glycan has a similarly critical role in multimeric, avidly binding Fcs, is unknown. Hexa-Fc contains two N-linked sites at Asn-77 (equivalent to Asn-297 in the Fc of IgG1) and Asn-236 (equivalent to Asn-563 in the tail piece of IgM). We report here that glycosylation at Asn-297 is critical for interactions with Fc receptors and complement and that glycosylation at Asn-563 is essential for controlling multimerization. We also found that introduction of an additional fully occupied N-linked glycosylation site at the N terminus at position 1 (equivalent to Asp-221 in the Fc of IgG1) dramatically enhances overall sialic acid content of the Fc multimers. Furthermore, replacement of Cys-575 in the IgM tail piece of multimers resulted in monomers with enhanced sialic acid content and differential receptor-binding profiles. Thus insertion of additional N-linked glycans into either the hinge or tail piece of monomers or multimers leads to molecules with enhanced sialylation that may be suitable for managing inflammation or blocking pathogen invasion.

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Section: Discussionmentioning

confidence: 99%

Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors

Blundell

Allen

et al. 2017

Journal of Biological Chemistry

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“…Also the direct application of ganglioside GM1 into the brain of patients with Alzheimer disease has been evaluated [ 338 ]. As indirect roles, the inhibition of ganglioside biosynthesis for the treatment of insulin resistance [ 339 ], the interference with microbial binding to gangliosides [ 340 ], or the reduction of neurotoxicity with Liga20 [ 341 ] has to be mentioned.…”

Section: Pathobiochemistrymentioning

confidence: 99%

Ganglioside Biochemistry

2012

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“…This may be a major reason why simple carbohydrates like IPTG and LAU only showed weak inhibition towards oral BoNT/A intoxication on mice. Therefore, it would be more desirable to develop multivalent carbohydrate inhibitors that simultaneously target multiple receptor-binding sites on the HA complex (Barthelson et al, 1998; Bernardi et al, 2013; Thomas, 2010). In fact, decavalent ligands against cholera toxin lead to a 106-fold increase in potency compared with monovalent Gal (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting oral intoxication of botulinum neurotoxin A complex by carbohydrate receptor mimics

Lee

Lam

Kruel

et al. 2015

Toxicon

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Botulinum neurotoxins (BoNTs) cause the disease botulism manifested by flaccid paralysis that could be fatal to humans and animals. Oral ingestion of the toxin with contaminated food is one of the most common routes for botulism. BoNT assembles with several auxiliary proteins to survive in the gastrointestinal tract and is subsequently transported through the intestinal epithelium into the general circulation. Several hemagglutinin proteins form a multi-protein complex (HA complex) that recognizes host glycans on the intestinal epithelial cell surface to facilitate BoNT absorption. Blocking carbohydrate binding to the HA complex could significantly inhibit the oral toxicity of BoNT. Here, we identify lactulose, a galactose-containing non-digestible sugar commonly used to treat constipation, as a prototype inhibitor against oral BoNT/A intoxication. As revealed by a crystal structure, lactulose binds to the HA complex at the same site where the host galactose-containing carbohydrate receptors bind. In vitro assays using intestinal Caco-2 cells demonstrated that lactulose inhibits HA from compromising the integrity of the epithelial cell monolayers and blocks the internalization of HA. Furthermore, co-administration of lactulose significantly protected mice against BoNT/A oral intoxication in vivo. Taken together, these data encourage the development of carbohydrate receptor mimics as a therapeutic intervention to prevent BoNT oral intoxication.

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Receptor mimicry as novel therapeutic treatment for biothreat agents

Cited by 24 publications

References 153 publications

Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors

Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors

Ganglioside Biochemistry

Inhibiting oral intoxication of botulinum neurotoxin A complex by carbohydrate receptor mimics

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