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WIREs Nanomed Nanobiotechnol
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Physical, chemical, and synthetic virology: Reprogramming viruses as controllable nanodevices

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The fields of physical, chemical, and synthetic virology work in partnership to reprogram viruses as controllable nanodevices. Physical virology provides the fundamental biophysical understanding of how virus capsids assemble, disassemble, display metastability, and assume various configurations. Chemical virology considers the virus capsid as a chemically addressable structure, providing chemical pathways to modify the capsid exterior, interior, and subunit interfaces. Synthetic virology takes an engineering approach, modifying the virus capsid through rational, combinatorial, and bioinformatics‐driven design strategies. Advances in these three subfields of virology aim to develop virus‐based materials and tools that can be applied to solve critical problems in biomedicine and biotechnology, including applications in gene therapy and drug delivery, diagnostics, and immunotherapy. Examples discussed include mammalian viruses, such as adeno‐associated virus (AAV), plant viruses, such as cowpea mosaic virus (CPMV), and bacterial viruses, such as Qβ bacteriophage. Importantly, research efforts in physical, chemical, and synthetic virology have further unraveled the design principles foundational to the form and function of viruses. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures
Quasi‐equivalence and triangulation numbers of icosahedrons. (a) The icosahedron can be displayed as a hexagonal lattice. The arrangement of the fivefold symmetry axes on this lattice gives the icosahedral shape its triangulation number, given as T = h2 + hk + k2, where h and k are vector coordinates (h, k ∈  ≥ 0) defining the points of the fivefold axes. (b) As an icosahedral shape gets larger, there are more subunits inside each equilateral triangle (blue outline), as shown by the T = 1 and T = 3 icosahedrons. All symmetrical contacts within the T = 1 are equivalent, while those in higher T numbers are not (J. E. Johnson & Speir, ). This quasi‐equivalence allows for conformational polymorphism of the subunits in higher T numbered icosahedral capsids. For example, in the T = 3 diagram even though A, B, and C subunits are virtually identical, the quasi‐equivalence of A–C and B–B contacts indicated in the figure have bent and flat contact angles, respectively. This gives the pentamers (red subunits) a bent surface and the hexamers (green subunits) a flat surface to form the icosahedral shape. (Reprinted with permission from Cheng et al. (). Copyright 1994 Elsevier)
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Example of bioinformatics‐driven capsid design. The reconstructed ancestral phylogeny of adeno‐associated virus (AAV) was used to develop a new mutant, Anc80. Anc80 is the ancestor of currently studied AAV serotypes excluding AAV4 and AAV5. The distance between viruses in the hierarchical chart denotes relative distance of relation between the viruses. (Reprinted with permission from Zinn et al. (). Copyright 2015 Elsevier)
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A combination of directed evolution and capsid structural information can enable the design of viruses with improved properties. (a) 3D cryo‐reconstructed image of an adeno‐associated virus (AAV) capsid with bound neutralizing antibodies (NAb). (b) Roadmap of where the antibodies bind to on the AAV capsid. Color codings of each antibody are same as in panel a with overlapping residues between antibodies colored individually: Green, ADK1a and 4E4; gray, 4E4 and 5H7. (c) Experimental plan for the directed evolution of three different capsid regions where antibodies bind. (d) Combination of the three viral libraries led to the generation of AAV‐CAM vectors. (Reprinted with permission from Tse et al. (). Copyright 2017 Creative Commons Attribution License)
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Reprogramming a conformational switch‐based output of the adeno‐associated virus (AAV) capsid. Truncated viral protein (VP) subunits with hexahistidine (his) tags at the N‐termini were generated based on the AAV capsid. Upon incubation at different temperatures, capsids with surface‐displayed his tags were captured with a nickel column. The wild‐type capsid undergoes the structural conformational change upon incubation at ~60°C. Depending on the composition of the mutant AAV capsids, some capsids display his tags prior to activation (always “ON”) whereas other capsids display activatable peptide display (“activatable”). (Reprinted with permission from Thadani et al. (). Copyright 2017 American Chemical Society)
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Examples of modifications at the capsid subunit interface. (a) Interactions that are found to play an important role in subunit–subunit interaction in the wild‐type capsid include electrostatic interactions, van der Waals forces, π‐stacking, and disulfide bonds. (b) Tyrosine residues can be crosslinked chemically to join nearby subunits. (c) Polymers spanning across multiple capsid subunits can also be used to crosslink the capsid
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Overview of internal capsid modifications. The capsid protein subunits can be modified before or after assembly for various purposes, such as internal surface functionalization, material encapsidation, and the creation of nanoreactors
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Examples of capsid bioconjugation approaches. (a) Simplified scheme of NHS‐ester conjugation, in which a molecule P can be attached to a free primary amine on the viral capsid through formation of an amide bond. (b) General scheme of maleimide conjugation, in which a molecule containing a maleimide group can react with a free sulfhydryl group on the protein capsid to yield a stable thioether bond. (c) Schematic of copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry. An azide and alkyne react in the presence of a copper‐based catalyst to form a triazole
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Capsid metastability and polymorphism. (a) Cowpea chlorotic mottle virus (CCMV) swells up when the solution pH is increased from pH 5 to 7 at low ionic strength without divalent cations, allowing larger pores to form on the capsid. These pores can be used to pack therapeutics or imaging agents inside the viral capsid for delivery. (Reprinted with permission from Liu et al. (). Copyright 2003 Elsevier). (b) Tobacco mosaic virus (TMV) particles of different lengths can be generated by assembly in vitro with RNA of different lengths with high‐affinity origins of assembly. The TMV particles of different aspect ratios can be visualized with electron microscopy. Scale bar is 100 nm. (Reprinted with permission from Shukla, Eber, et al. (). Copyright 2015 John Wiley and Sons)
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Biology-Inspired Nanomaterials > Protein and Virus-Based Structures
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