Molecular "Slingshot" Takes Aim at Disease

Simple but effective, the slingshot has been used in warfare, hunting, and general mischief-making throughout history. In the 1st Century A.D., eagle-eyed sharpshooters of the Roman Empire’s invading armies took slinging to a lethal new level, hurling hollow-point lead balls with the force of a modern .44 magnum. Today, ancient Roman history is repeating itself as chemists at the University of Rome Tor Vergata are adapting the ancient power of the sling for a new battle against modern health threats like HIV.

Based on recent ballistic evidence from a 1,900-year-old battlefield in Scotland, a top-notch Roman slinger could nail a human-sized target at a distance of 130 yards. But even that uncanny accuracy has nothing on Prof. Francesco Ricci’s molecular slingshot, which is designed to target and neutralize infectious pathogens with laser precision. The experimental drug delivery system draws comparisons to a slingshot for good reason – it looks and works pretty much like the real thing, only about 20,000 times smaller than the diameter of a human hair.

The familiar modern slingshot comprises a rubber band stretched between the two arms of a Y-shaped frame. The shooter positions a projectile on the band, pulls it back, takes aim, and releases it. In place of the rubber band, the molecular slingshot uses a strand of synthetic DNA to which an infection-fighting drug compound has been affixed. Each end of this strand is also chemically programmed to recognize and bind together with specific infection-fighting antibodies – the Y-shaped protein molecules expressed by the immune system in response to viral or bacterial threats. So like an actual slingshot, the DNA strand stretches across the gap between the two arms of the antibody, creating a rubber band-like firing mechanism. As it stretches, the band releases the drug compound at the exact site of infection.
 
Working with colleagues from the University of Montreal, Ricci’s team synthesized unusual triplex-forming DNA sequences to serve as the rubber band. As the team reported in a recent study in Nature Communications, these triplex sequences possess a third helix, which the group used to form a clamp-like structure for holding a drug compound. As the DNA strand anchors itself to the antibody, it undergoes a conformational change that disrupts its complex chemical architecture, thus releasing the therapeutic payload.

Going Ballistic

In what Ricci calls “one of the most exciting research paths in nanotechnology and supramolecular chemistry,” several groups around the world have recently described increasingly complex nanodevices for biomedical applications such as controlled drug release, signal transduction, and sensing. The bioengineer’s Angstrom-scale arsenal is already stocked with nano-bullets, acoustic microcannons, and other ballistic weapons aimed at cancer, viruses, and other diseases. All of them work when the device senses the presence of a specific molecular input from a known disease biomarker, for example, an abnormal level of a certain gene, enzyme, or hormone in blood or tissue. The molecular slingshot is one of the few approaches based on antibodies as the regulatory input.

“While many examples have been reported where the release of DNA strands can be controlled by several molecular clues – that, is, pH, proteins, and so on – the possibility to use antibodies as a triggering input might open new routes in the field of DNA nanotechnology,” Ricci said. The group has demonstrated the working principle on three antibodies, including HIV, and has used nucleic acids as model drugs. But through advanced DNA chemistry, it’s possible to design slingshots that fire a variety of drug molecules. “Because antibodies represent a wide class of clinical and diagnostic markers, (our nanomachines) may be useful in a range of applications, including point-of-care diagnostics, controlled drug release and in vivo imaging.” As the work advances toward human applications, he said, the group will begin preclinical testing specific drugs against specific diseases.

The potential human impacts of these studies are significant. The ability to deliver drugs precisely where they’re needed in the body enables doctors to use smaller, less toxic doses of stronger drugs – they can take out the disease without taking out the patient, too. Lowering the physical, emotional, and financial impacts of treating life-threatening diseases like AIDS and cancer also reduces the burdens of these widespread diseases on patients, their families, and society as a whole. Although the ideas come from ancient times, those are goals that Caesar himself would hail.

Michael MacRae is an independent technical writer based in Portland, OR.