Multivalency in Ligand Design

Severity of peanut allergies is linked to allergen-specific immunoglobulin E (IgE) antibodies in blood, but diagnostics from assays using glycoprotein allergen mixtures may be inaccurate. Measuring IgEs specific to individual peptide and carbohydrate epitopes of allergenic proteins is promising. We report here the first immunoarray for IgEs utilizing both peptide and carbohydrate epitopes. A surface plasmon resonance imaging (SPRi) microarray was equipped with peptide and β-xylosyl glycoside (BXG) epitopes from major peanut allergen glycoprotein Arachis hypogaea h2 (Ara-h2). A monoclonal anti-IgE antibody was included as positive control. IgEs were precaptured onto magnetic beads loaded with polyclonal anti-IgE antibodies to enhance sensitivity and minimize non-specific binding. As little as 0.1 attomole (0.5 pg/mL) IgE was detected from dilute serum in 45 min. IgEs binding to Ara-h2 peptide and BXG were quantified in 10 μL of patient serum and correlated with standard ImmunoCAP values.

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“…Strong avidity between IgEs and surface ligand spots could possibly be influenced by the bivalent nature of IgE antibodies. 27 …”

Section: Resultsmentioning

confidence: 99%

Ultrasensitive carbohydrate-peptide SPR imaging microarray for diagnosing IgE mediated peanut allergy

Joshi

Peczuh

Kumar

et al. 2014

Analyst

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“…In multisite interactions, greater than additive increases in binding strength without changes in effective binding stoichiometry are a signature of avidity effects. 35 Conjugation to P1 or P2 slows down QK release from MITCH by affinity immobilization…”

Section: Avidity Increases the Binding Strength Of P2 Affinity Tags Rmentioning

confidence: 99%

“…By linking two P1 domains with a tetraglycine spacer, we engineered P2 to have stronger interactions than P1 due to avidity, or binding synergy from having multiple binding sites. 35 The tetraglycine spacer confers conformational flexibility but is hypothesized to be too short to allow both P domains to bind two C domains simultaneously. ITC was employed to evaluate these hypotheses ( Supplementary Fig.…”

Section: Avidity Increases the Binding Strength Of P2 Affinity Tags Rmentioning

confidence: 99%

Avidity-Controlled Delivery of Angiogenic Peptides from Injectable Molecular-Recognition Hydrogels

Mulyasasmita

Cai

Hori

et al. 2014

Tissue Engineering Part A

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Peptide mimics of growth factors represent an emerging class of therapeutic drugs due to high biological specificity and relative ease of synthesis. However, maintaining efficacious therapeutic dosage at the therapy site has proven challenging owing to poor intestinal permeability and short circulating half-lives in the blood stream. In this work, we present the affinity immobilization and controlled release of QK, a vascular endothelial growth factor (VEGF) mimetic peptide, from an injectable mixing-induced two-component hydrogel (MITCH). The MITCH system is crosslinked by reversible interactions between WW domains and complementary proline-rich peptide modules. Fusion of the QK peptide to either one or two units of the proline-rich sequence creates bifunctional peptide conjugates capable of specific binding to MITCH while preserving their angiogenic bioactivity. Presenting two repeats of the proline-rich sequence increases the binding enthalpy 2.5 times due to avidity effects. Mixing of the drug conjugates with MITCH components results in drug encapsulation and extended release at rates consistent with the affinity immobilization strength. Human umbilical vein endothelial cells (HUVECs) treated with the soluble drug conjugates exhibit morphogenetic events of VEGF receptor 2 signal transduction followed by cell migration and organization into networks characteristic of early angiogenesis. In a three-dimensional model where HUVECs were cultured as spheroids in a matrix of collagen and fibronectin, injection of drug-releasing MITCH resulted in significantly more cell outgrowth than drugs injected in saline. This ability to sustain local drug availability is ideal for therapeutic angiogenesis applications, where spatiotemporal control over drug distribution is a key requirement for clinical success.

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“…In recent years, there has also been a tremendous interest in the design of novel polyvalent molecules (Badjic et al, 2005;Kane, 2006;Kiessling et al, 2006;Krishnamurthy et al, 2006;Mammen et al, 1998;Mulder et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Polyvalency: A promising strategy for drug design

Vance

Shah

Joshi

et al. 2008

Biotech & Bioengineering

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The simultaneous binding of multiple ligands on one entity to multiple receptors on another can result in an affinity that is significantly greater than that for the binding of a single ligand to a single receptor. This concept of ''polyvalency'' can be used to design molecules that are potent inhibitors of toxins and pathogens. We describe the design of potent polyvalent inhibitors that neutralize anthrax toxin in vivo as well as our attempts to elucidate the relationship between inhibitor structure and activity. We also highlight promising future avenues for research in polyvalent drug design.

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Multivalency in Ligand Design

Cited by 142 publications

References 160 publications

Ultrasensitive carbohydrate-peptide SPR imaging microarray for diagnosing IgE mediated peanut allergy

Ultrasensitive carbohydrate-peptide SPR imaging microarray for diagnosing IgE mediated peanut allergy

Avidity-Controlled Delivery of Angiogenic Peptides from Injectable Molecular-Recognition Hydrogels

Polyvalency: A promising strategy for drug design

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