P&S Journal: Fall 1996, Vol.16, No.3
Targeting Enveloped Viruses
Scientists have long sought a way to harness targeted toxins for therapeutic use against pathological cells. The effort, however, has been fraught with problems. Most toxins are not well- targeted, or, if they reach their targets, cannot make it past cell membranes to be effective. Now, a new strategy that uses a toxin from the venom of the snake Bungarus multicinctus is helping Dr. Peter D. Kwong, postdoctoral research scientist, and Dr. Wayne A. Hendrickson, Howard Hughes Medical Institute investigator and professor of biochemistry and molecular biophysics, design a targeted toxin with the potential to act on enveloped viruses. Their work was published in the Oct. 15, 1995, issue of Structure.
The toxin, §-bungarotoxin, is a presynaptic neurotoxin with targeting and enzymatic action contained in separate units. The Kunitz subunit of the toxin guides it to its site of action at the neuromuscular junction because of its high affinity interaction with a voltage-sensitive potassium channel. Once the toxin is properly located, a phospholipase subunit catalytically degrades the presynaptic membrane, blocking nerve transmission. The snake toxin is highly specific, causing complete paralysis without any significant side effects. This specificity helps make the snake toxin suitable for therapeutic adaptation.
In a design for which a patent application has been filed, Dr. Kwong and colleagues propose switching the targeting unit of the toxin to aim it not against presynaptic membranes but against enveloped viruses. Such a targeting is ideal, says Dr. Kwong, because phospholipases degrade extracellular membranes, and the virions of enveloped viruses do not have cellular biosynthetic mechanisms to repair the degradation. This makes enveloped viruses, which include HIV, herpes, influenza, and leukoviruses, particularly susceptible, says Dr. Kwong.
Dr. Kwong has prepared a conjugate of the separated bungarotoxin phospholipase linked to a recombinant soluble form of CD4, the primary receptor for HIV. When CD4 binds to its receptor on HIV, the phospholipase would attack the membrane of the virus, thereby killing it. Preliminary tests carried out by AIDS researcher Dr. Quentin J. Sattentau show this conjugate works at least 10 times better than dextran sulfate, a common benchmark of HIV inhibition. The researchers are now focusing on preparing more potent conjugates.
"If we could use this therapy to reduce the number of active virions, we might be able to change AIDS from a fatal disease to one that is merely chronic and manageable," says Dr. Kwong. The idea of using targeted toxins is not new, he adds, but this method allows it to target virions, which are resistant to conventional drugs. "We're taking an old technology and putting a new wrinkle in it by using a natural 'machine' that kills animals and adapting it to kill viruses."