Recent Advances in Engineering Polyvalent Biological Interactions

Varner, Chad; Rosen, Tania; Martin, Jacob T.; Kane, Ravi S.

doi:10.1021/bm5014469

Cited by 63 publications

(68 citation statements)

References 115 publications

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“…Our results demonstrate that, due to superselectivity and tunability, multivalent polymers have the potential to serve as versatile probes in biomedical applications, such as the design of efficient polymeric drugs and drug delivery systems. The presented approach, combining experiments and theory, should also be instructive to develop methods for the rational design of the targeting properties of other types of multivalent probes that are widely used in the field of nanomedicine, such as nanoparticles, nanocapsules, or liposomes (29). Moreover, the insights gained from the present study enhance our understanding of naturally occurring multivalent interactions, such as those between HA and cell surfaces.…”

Section: Discussionmentioning

confidence: 80%

Designing multivalent probes for tunable superselective targeting

Dubacheva

Curk

Auzély‐Velty

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

118

210

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Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such "superselective" binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer's superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44-hyaluronan interactions.tunability | superselectivity | host-guest multivalent interactions | hyaluronan

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Section: Discussionmentioning

confidence: 80%

Designing multivalent probes for tunable superselective targeting

Dubacheva

Curk

Auzély‐Velty

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

118

210

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“…Our study should extend the practical applications of the SAv/biotin technology, in particular in the design of robust biomimetic and bioactive supramolecular assemblies at interfaces. The obtained knowledge about the interplay between surface chemistry, binding stability and residual valency should also be useful to control surface binding of other rigid multivalent scaffolds (i.e., proteins, nanoparticles, and dendrimers), 3 thus contributing to the general understanding of multivalent interactions and their progressive use in nanobiotechnology.…”

Section: Discussionmentioning

confidence: 99%

“…1 Multivalent interactions are also an attractive tool for the design of supramolecular architectures, because they enable strong but reversible attachment, while drastically increasing binding selectivity as compared to monovalent bonds. 2,3 Defining the factors governing multivalent binding at interfaces is therefore important for understanding biological systems and for the design of supramolecular nanomaterials. 1−3 In particular, the dependence of multivalent self-assembly on surface properties (chemistry, packing, lateral mobility) remains difficult to assess.…”

Section: Introductionmentioning

confidence: 99%

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Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

et al. 2017

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Although multivalent binding to surfaces is an important tool in nanotechnology, quantitative information about the residual valency and orientation of surface-bound molecules is missing. To address these questions, we study streptavidin (SAv) binding to commonly used biotinylated surfaces such as supported lipid bilayers (SLBs) and self-assembled monolayers (SAMs). Stability and kinetics of SAv binding are characterized by quartz crystal microbalance with dissipation monitoring, while the residual valency of immobilized SAv is quantified using spectroscopic ellipsometry by monitoring binding of biotinylated probes. Purpose-designed SAv constructs having controlled valencies (mono-, di-, trivalent in terms of biotin-binding sites) are studied to rationalize the results obtained on regular (tetravalent) SAv. We find that divalent interaction of SAv with biotinylated surfaces is a strict requirement for stable immobilization, while monovalent attachment is reversible and, in the case of SLBs, leads to the extraction of biotinylated lipids from the bilayer. The surface density and lateral mobility of biotin, and the SAv surface coverage are all found to influence the average orientation and residual valency of SAv on a biotinylated surface. We demonstrate how the residual valency can be adjusted to one or two biotin binding sites per immobilized SAv by choosing appropriate surface chemistry. The obtained results provide means for the rational design of surface-confined supramolecular architectures involving specific biointeractions at tunable valency. This knowledge can be used for the development of well-defined bioactive coatings, biosensors and biomimetic model systems.

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“…Several examples of engineering polyvalent biological interactions have been described (68), and specific examples where polyvalency increases the potency of fusion inhibitors (69,70) or entry inhibitors (17) have been reported. For HRC fusion inhibitors, dimerization/multimerization (45,53) reduces the k off of the inhibitor-fusion protein complex formation in an effect that has been termed the "avidity effect" (71).…”

Section: Figmentioning

confidence: 99%

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

Figueira

Palermo

Veiga

et al. 2017

J Virol

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Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo. We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The selfassembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides.IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides.

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Recent Advances in Engineering Polyvalent Biological Interactions

Cited by 63 publications

References 115 publications

Designing multivalent probes for tunable superselective targeting

Designing multivalent probes for tunable superselective targeting

Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

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