Medical Applications of Nanotechnology: Nanobodies
University of California, San Diego
This is an abstract
for a presentation given at the
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.
- Ed Regis (1995) Nano the emerging science of technology, pages 230-252.
"are molecules sacred?"
- K. Peter C. Vollhardt; Neil E. Schore (1994) Organic Chemistry 2nd
edition, pages 106-128. Cyclic Alkanes
- Gregory M Fahy, (1992) Nanotechnology, ch 12 pages 251-263. Possible
Medical Applications of Nanothchnology: Hints from the Field of Aging Research
Bioengineer Senior at University of California, San Diego
281 Falcon Place, San Diego, Ca, 92103