Biomod/2014/NTU/Idea

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Motivation

Our immune system protects us from invading pathogens, and ensures that we recover in the event of an infection. However, it occasionally malfunctions and succumbs to these pathogens, resulting in dire consequences for our health. Our immune system certainly needs a booster in the wake of these ever-evolving microbes. Our project therefore aims to design a versatile device that can be tailored to target a wide range of microbes, thus complementing and enhancing our immune system.

Versatility

To allow our device to be versatile in recognizing and binding different targets, we have incorporated the idea of aptamers into the design. Aptamers are oligonucleotides that are able to bind to specific target molecules. By changing specific aptamers attached to the scaffold, the device could be tailored to bind to a range of different targets, and thus be applied to treat different types of diseases. This versatility to bind to different targets, and would certainly be a great boost for therapeutic medicine.

Immune enhancement

For immune enhancement, we have designed the structure and shape of the device such that it resembles that of a jellyfish - with a head and tentacles. The jellyfish will be able to accomplish three sequential tasks: one to capture target pathogen, two to release the package molecules upon binding, and three undergo aggregation. This idea is itself ground-breaking because it incorporates three modes of defense into one. It will not only neutralize the pathogen, stimulate immune response, but also localize the infection. This “three-in-one” device thus provides a revolutionary standpoint in how we treat diseases.

Fighting the influenza virus

In this project, we hope to use our device to better fight the influenza virus. But why influenza in particular?

Influenza: a constant pain

For most people, the term influenza is often synonymous with the common cold, due largely to the symptoms that they share. However, the influenza is in fact more deadly. The seasonal flu causes thousands of deaths every year, while past pandemics have created devastating impacts on the human population, with the 1918 Spanish flu being the most notorious in recent history¹.
As the influenza virus constantly develops new variants via mechanisms of antigenic drift and antigenic shift, we have to be on the search for novel methods to counteract the virus. With this in mind, we have decided to tailor our nanojellyfish towards fighting the influenza virus. The hemagglutinin type 5 (H5) protein present on the surface of the influenza virus is chosen as our target because there has been numerous outbreaks of H5N1 in recent years², and a H5-linked pandemic is likely.

Problems with current strategies

There are currently two strategies in combating influenza. One is through vaccination, where an individual receives protective immunity against the seasonal flu. The other is through antiviral drugs, which prevent the flu virion from replicating. Even though these two strategies have worked considerably well since their development, there are still several drawbacks that have kept influenza a constant pain.
The problem with vaccination is that current production of egg-based vaccines is still laborious, requiring a minimum of six months for a new vaccine to be made³. This implies that effective vaccines may not be readily available when new viruses emerge, making outbreaks of pandemic influenza particularly dangerous. Besides, protein-based vaccines are sensitive to environmental fluctuations and require sophisticated storage and transport.
On the other hand, the potency and effectiveness of current antiviral drugs is beginning to raise questions, as drug-resistant variants continually emerge. The rise of Oseltamivir-resistant H1N1 strains in 2009 is testament to the need to develop new and novel drugs that can fight the flu virus4.

Nanojellyfish as a new paradigm

Our nanojellyfish aims to circumvent the problems with the current strategies. The use of a DNA-based scaffold confers extra drug stability and provides easy storage, and the ease of linking differing aptamers to the DNA scaffold allows rapid production. Meanwhile, the features of capture, release, and aggregation provides a new arsenal in light of viral drug resistance. Our nanojellyfish will provide a new paradigm in fighting the ever-changing influenza virus.
The hallmark of our device lies in the features of capture, release, and aggregation. It is therefore important to align our goals according to these three features.

Capture: The nanojellyfish dimer is able to bind and capture target virus.

Release: The nanojellyfish dimer is able to packaged protein molecule, and upon binding target virus, open up and release packaged protein molecule.

Aggregation: The virus-bound monomer is able to undergo aggregation

1.Beigel, J. H. (2008). Concise Definitive Review: Influenza. Crit Care Med, 2660–2666.
2.David A. Boltz, J. R. (2010). Drugs in Development for Influenza. Drugs, 1349-1362.
3.Disease, N. I. (2011). Timeline of Human Flu Pandemics. National Institute of Allergy and Infectious Disease.
4.Organization, W. H. (2009). Pandemic influenza vaccine manufacturing process and timeline. Pandemic (H1N1) 2009 briefing note 7. Geneva: World Health Organization.

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