Artificial Virus
DOI: 10.1002/anie.200800266
Filamentous Artificial Virus from a Self-Assembled DiscreteNanoribbon**
Yong-beom Lim, Eunji Lee, You-Rim Yoon, Myeong Sup Lee, and Myongsoo Lee*
The creation of virus-like nanomaterials (artificial viruses)has been the subject of intensive research in the field of gene/drug delivery because of their huge therapeutic potential.
Some progress has been made in the field; however,compared to the natural viruses, which are evolution-tailoredexperts in gene delivery, the synthetic system is still far behindthe natural system. One of the critical reasons for thisshortcoming is that the size and shape of the artificial viruses,among the most important determinants of their efficiency,are very difficult to control.As the polyanionic nature of nucleic acids (DNA andRNA) prevents them from crossing the same chargedcytoplasmic membrane barrier, a vector system is necessaryto neutralize their charge and to install other functions, suchas cell binding, endosome escape, and nucleus localization.Although there are serious safety concerns, such as immuno-genicity and carcinogenesis, in the use of viral vectors, theyare still far more widely used for gene therapy than nonviralvectors (artificial viruses) because of their higher efficiency.
The basic principle of artificial virus formation is acondensation reaction which is induced by the attractionbetween oppositely charged molecules (for example, betweencationic polymer and DNA).
However, this polyion cou-pling generally leads to the formation of huge nanoaggregatesthat are highly heterogeneous in size and shape, and isuncontrollable in most cases.
In regard to the size issue, acertain optimal size exists for the nanoparticulate deliverysystems to work best. The shape of the nanoparticle can alsobe a crucial factor. For example, sometimes the cylindrical(that is, filamentous) nanostructure has certain advantagesover the spherical one in that it persists longer in vivo,
whichmight explain why many filamentous viruses exist in nature.Therefore, it is imperative to find a general strategy to controlthe size and shape of artificial viruses.Recent advances in supramolecular chemistry have madeit possible, by rational design of building blocks, to controlsupramolecular architectures from spherical micelles, cylin-drical micelles, vesicles, and toroids to nanotubes.
Inspiredby this elaboration, we envisioned that the control of the sizeand shape of artificial viruses would be possible if thepreorganized supramolecular architectures used were robustpolycationic scaffolds that remain unchanged after theformation of an interpolyelectrolyte complex (IPC) withnegatively charged nucleic acids. Herein, we report a poten-tially generalizable strategy to create an artificial virus thatmemorizes the size and shape of its precursor. By using apreorganized supramolecular nanostructure as a template, weshow that well-defined, discrete artificial viruses can beelaborated after IPC formation between the nanostructureand nucleic acids. This controlled feature and appropriatesurface functionalization with multivalent carbohydrateligands make the artificial virus highly efficient in theintracellular delivery of genes and drugs.With the aim of constructing filament-shaped, discreteartificial viruses, a
b
-sheet peptide-based supramolecularbuilding block (Glu-KW) was designed (Figure 1a). To ourknowledge the filament-shaped artificial virus is unprece-dented. It has been shown that the combination of hydro-phobic and electrostatic interactions produced by the alter-nating placement of hydrophobic and charged amino acids in
b
-sheet peptides promotes
b
-sheet interactionand subsequentself-assembly into bilayered filamentous nanostructures(
b
ribbon).
Coupling of hydrophilic segments, such aspolyethylene glycol, hydrophilic peptides, or carbohydrates,to
b
-sheet peptides has been reported to stabilize
b
-ribbonnanostructures by suppressing lateral aggregate forma-tion.
The Glu-KW structure is characterized by a
b
-sheet-forming self-assembly segment, two linker segments, a nucleicacid-binding cationic segment, and a carbohydrate ligandsegment. The
b
-sheet peptide segment consists of trypto-phan–lysine–tryptophan–aspartic acid repeats, the amino acidconfiguration of which promotes
b
-sheet formation. Thelinker segments are designed to be flexible and nonionic byusing glycine and serine residues. The eight lysine residues areplaced between two linker segments to shield the cationicsegment, upon self-assembly, from the
b
-ribbon surface.
d-
Glucose is positioned at the outermost part of Glu-KW torender the
b
-ribbon surfacecharge-neutralandtoincreasethechances of
b
-ribbon binding to the cell surface throughmultivalent interactions
with cell-surface glucose trans-porters (GLUTs). GLUTs are present in nearly all mamma-lian cells and overexpressed in most cancer cells.
To address the question of whether Glu-KW forms
b
-sheet-mediated nanostructures, the self-assembly of Glu-KWwas investigated by circular dichroism (CD) and transmission
[*] Dr. Y.-b. Lim, E. Lee, Y.-R. Yoon, Prof. M. LeeCenter for Supramolecular Nano-Assembly andDepartment of ChemistryYonsei University, Seoul 120-749 (Korea)Fax: (
+
82)2-393-6096E-mail: mslee@yonsei.ac.krHomepage: http://csna.yonsei.ac.krDr. M. S. LeeDepartment of Biochemistry, Yonsei University (Korea)[**] We gratefully acknowledge the National Creative Research InitiativeProgram of the Korean Ministry of Science and Technology forfinancial support of this work.Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.
Angewandte
Chemie
4525
Angew. Chem. Int. Ed.
2008
,
47
, 4525–4528 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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