This virus can potentially be used for the delivery of new generations of pharmaceuticals, consisting of large biomolecules, by ‘packaging’ them in a natural fashion and delivering them to diseased cells. The artificial virus was designed according to new theoretical insights into how viruses operate and offers prospects for the delivery of pharmaceuticals, write the researchers in the latest online edition of Nature Nanotechnology. In particular, the researchers believe that the artificial virus technology could be potentially useful for gene therapy.
Traditional pharmaceuticals consist of relatively small molecules that typically end up at the desired location without too much trouble. This is more difficult for newer types of drugs that are being developed; these consist of large biomolecules such as proteins and genetic material (i.e. DNA and RNA). For example, to use DNA in gene therapy, the molecule must be delivered to diseased cells in its entirety to be effective. However, DNA is inherently incapable of penetrating cells and is quickly degraded. Therefore natural viruses that have been rendered harmless are used as so-called vectors. These can enter cells efficiently and deliver the therapeutic DNA or RNA molecules. However, the process of rendering natural viruses harmless still requires improvement. Unintended side effects have been a problem. Therefore, research is also being conducted into alternative ‘virus-like’ vectors based on synthetic molecules. Unfortunately, these have been less effective because it is difficult to precisely imitate the many tricks used by viruses. A first important step in mimicking viruses is the precise packaging of individual DNA molecules with a protective coat of smaller molecules. This sounds simpler than it is, the researchers say. Until now, packaging individual DNA molecules with a protective coating of synthetic molecules has not yet been achieved.
Artificial viral coat proteins
Instead of using synthetic chemistry to coat individual DNA molecules, the researchers decided to design and produce artificial viral coat proteins. As part of their study, they used recent theoretical insights into the crucial aspects of the process of packaging genetic material by natural viral coat proteins. The researchers ‘translated’ each of these crucial aspects into various protein blocks with simple structures. The amino acid sequence of the protein blocks was inspired by natural proteins such as silk and collagen. Artificial viral coat proteins designed in this way were produced using the natural machinery of yeast cells. When the proteins were mixed with DNA, they spontaneously formed a highly protective protein coat around each DNA molecule, thus creating ‘artificial viruses’. The formation process of the artificial viruses is similar in many ways to that of natural viruses, such as the tobacco mosaic virus, which served as a model for the artificial virus.
This first generation of artificial viruses was found to be as effective as the current methods for delivering DNA to host cells based on synthetic molecules. But the great precision by which DNA molecules are packaged in the artificial virus offers many possibilities to now also build in other virus tricks, the researchers write. In the future, these techniques can hopefully lead to safe and effective methods for delivering new generations of pharmaceuticals, especially in gene therapy. Moreover, these artificial viruses can also be developed for the many other applications in which viruses are now being used in fields such as biotechnology and nanotechnology.
The artificial viral proteins were designed and produced by scientists of Wageningen UR (University & Research centre). They worked in collaboration with partners from Eindhoven University of Technology and Leiden University, who provided contributions based on the theory of spontaneous formation of virus particles and helped to visualise the resulting artificial virus particles, and partners from Radboud University Nijmegen, who studied the penetration of the artificial virus particles into living cells.