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Design of Multivalent Inhibitors for Preventing Cellular Uptake.

ABSTRACT: Cellular entry, the first crucial step of viral infection, can be inhibited by molecules adsorbed on the virus surface. However, apart from using stronger affinity, little is known about the properties of such inhibitors that could increase their effectiveness. Our simulations showed that multivalent inhibitors can be designed to be much more efficient than their monovalent counterparts. For example, for our particular simulation model, a single multivalent inhibitor spanning 5 to 6 binding sites is enough to prevent the uptake compared to the required 1/3 of all the receptor binding sites needed to be blocked by monovalent inhibitors. Interestingly, multivalent inhibitors are more efficient in inhibiting the uptake not only due to their increased affinity but mainly due to the co-localization of the inhibited receptor binding sites at the virion's surface. Furthermore, we show that Janus-like inhibitors do not induce virus aggregation. Our findings may be generalized to other uptake processes including bacteria and drug-delivery.

SUBMITTER: Schubertova V

PROVIDER: S-EPMC5601900 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Design of Multivalent Inhibitors for Preventing Cellular Uptake.

Schubertová Veronika V Martinez-Veracoechea Francisco J FJ Vácha Robert R

Scientific reports 20170915 1

Cellular entry, the first crucial step of viral infection, can be inhibited by molecules adsorbed on the virus surface. However, apart from using stronger affinity, little is known about the properties of such inhibitors that could increase their effectiveness. Our simulations showed that multivalent inhibitors can be designed to be much more efficient than their monovalent counterparts. For example, for our particular simulation model, a single multivalent inhibitor spanning 5 to 6 binding site ...[more]

PMID: 28916832

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Project description:From the authors' opinion, this chapter constitutes a modest extension of the seminal and inspiring contribution of Stowell and Lee on neoglycoconjugates published in this series [C. P. Stowell and Y. C. Lee, Adv. Carbohydr. Chem. Biochem., 37 (1980) 225-281]. The outstanding progresses achieved since then in the field of the "glycoside cluster effect" has witnessed considerable creativity in the design and synthetic strategies toward a vast array of novel carbohydrate structures and reflects the dynamic activity in the field even since the recent chapter by the Nicotra group in this series [F. Nicotra, L. Cipolla, F. Peri, B. La Ferla, and C. Radaelli, Adv. Carbohydr. Chem. Biochem., 61 (2007) 353-398]. Beyond the more classical neoglycoproteins and glycopolymers (not covered in this work) a wide range of unprecedented and often artistically beautiful multivalent and monodisperse nanostructures, termed glycodendrimers for the first time in 1993, has been created. This chapter briefly surveys the concept of multivalency involved in carbohydrate-protein interactions. The topic is also discussed in regard to recent steps undertaken in glycobiology toward identification of lead candidates using microarrays and modern analytical tools. A systematic description of glycocluster and glycodendrimer synthesis follows, starting from the simplest architectures and ending in the most complex ones. Presentation of multivalent glycostructures of intermediate size and comprising, calix[n]arene, porphyrin, cyclodextrin, peptide, and carbohydrate scaffolds, has also been intercalated to better appreciate the growing synthetic complexity involved. A subsection describing novel all-carbon-based glycoconjugates such as fullerenes and carbon nanotubes is inserted, followed by a promising strategy involving dendrons self-assembling around metal chelates. The chapter then ends with those glycodendrimers that have been prepared using commercially available dendrimers possessing varied functionalities, or systematically synthesized using either divergent or convergent strategies.

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Design of Multivalent Inhibitors for Preventing Cellular Uptake.

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Design of Multivalent Inhibitors for Preventing Cellular Uptake.

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