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University of California, San Diego
This is an abstract for a presentation given at the
Sixth Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is available on the web.
Abstract: The AIDS virus has been studied and its effects on the immune system have been found to cripple the T-cell and antibody immune response. The very cells that mediate the immune response are attacked and duped into becoming HIV factories to further accelerate and spread the deadly virus. Modern AIDS "drug cocktails" have greatly slowed the growth and spread of the virus but still there is no tool in the arsenal for attacking the virus directly. They have proven too small to attack and destroy. Nanotechnology offers a new way to look at the problem.
Without the T-4 cell the antibody response is not mediated and is a slow and unsuccessful response, unable to stop the tiny viruses. Through the prospects of nanotech, it is possible to evoke the response of another part of the body's immune system. A immune response that does not need the conformation of the T-cells to attack and destroy. The blood carries within it the Complement. This is a collection of proteins that will collect and engulf an invading protein, bacteria or other foreign particle. This neutralizes the object until a macrophage comes by to engulf and digest the whole package. The complement is a cascade event. It begins with an initial reaction, often mediated by an antibody and then a series of catalysts and reactions assemble the proteins around the object. The complement is most commonly used to attack bacteria.
There is a short circuit in the complement cascade. There are certain protein coats on some bacteria that stimulate a response of the 3b protein of the cascade. This response is not mediated by anything and has nothing to do with the T-cells and the antibodies. This is where I propose that a device can be engineered to attach to the HIV "head" and undergo a conformation change to expose a previously covered protein coat that will induce the short 3b cascade in the complement. The device and the HIV are engulfed by the complement and eventually destroyed by the scavenging white blood cells.
The design has four major aspects to it. First is the molecular hinge needed for the two conformations the molecular device has. The cyclohexane ring is proposed for this. The carbon backbones of the bulb and tweezer parts are attached to this ring and the binding to an HIV by the tweezer arms will cause a change in conformation to the form that will elicit a complement response. The tweezer arms are the second major part of the structure. Through research, a series of atoms can be designed to act as a bonding site for a specific part of the HIV. This bonding will attach the HIV to the nanobody and cause the cyclohexane ring to change conformation to the opposite chair conformation. All axial bonds switch to equatorial bonds and all equatorial swing to axial bonds. This orientation change can be used to cause the opening of the bulb part of the device. The bulb part will be mechanically similar to the workings of a flower's petals. As the tweezer end bonds the bulb part opens (its axial bonds now lie in the equatorial plane). This will expose the fourth part of the device. The protein fragment is contained inside the bulb part. It is of the class of proteins that cause the 3b cascade and research is needed to determine the best protein to use. Since this device is of such small scale, a small fragment will be needed.
Full size drawing
The production of the nanobody is currently a slow process, manipulation of single atoms is all that is possible right now. But prototypes can be feasibly made for testing purposes. Assemblers will be needed to create the vast numbers needed to mount a reasonable offense. The device must not elicit the complement's response until it has bonded to the HIV. Then the nanobody changes its conformation and, like a beacon, flags the small virus for the complement to engulf and remove. The drawings in this abstract show four "arms" for the bulb and tweezer parts. Most likely only three arms will make up the bulb and tweezer assemblies. This is because of the six possible axial bonds, only three will be orientated in the right direction. (three point north, three point south so to say) The same can be said for the equatorial bonds, only three will change to axial in the proper rotation direction.
I hope to research the methods of binding to small virus protein coats and having this binding cause a conformation change to open the bulb part of the nanobody. The proper protein candidate to enclose in the bulb section. Proper understanding of the 3b cascade in the complement will bring this device to reality. A failsafe deactivation of the device can be designed as well. An insect hormone can be used to also cause the conformation change and bring the complement to remove all nanobodies. This failsafe site can be designed to bind to a completely different part of the nanobody. Possibly binding to the outside of the tweezer arms. Insect hormones are unrecognized by the human body, but other compounds might prove to be more effective.
Bioengineer Senior at University of California, San Diego
281 Falcon Place, San Diego, Ca, 92103