Researchers from the University of Chicago and the Massachusetts Institute of Technology are now working to develop the next generation of anti-viral treatments. Although, the molecular process by which an anti-HIV drug induces lethal mutations in the virus’s genetic material is especially difficult to study, it is now being clarified by a newly developed spectroscopy method.
Viruses can mutate rapidly in order to adapt to environmental pressure, which makes them resistant to anti-viral drugs. Andrei Tokmakoff, the Henry G. Gale Distinguished Service Professor in Chemistry at UChicago, recognising the stealthy nature of viruses said, “You need something sneaky, something that the virus isn’t going to recognize as a problem.” And that is exactly what they came up with – A strategy that uses the viruses’ own mechanism against them. This strategy, called lethal mutagenesis seeks to extinguish viruses by forcing their already high mutation rates above an intolerable threshold. If viruses experience too many mutations, they can’t properly manage their genetic material. Using lethal mutagenesis scientists have developed therapeutic anti-viral agents for HIV, Hepatitis C, and influenza.
KP1212, is a lethally mutagenic molecule designed to resemble natural DNA bases, the adenine-thymine, cytosine-guanine base pairs.These analogs can bind to the wrong base partners and therefore lead to genetic mutations. A leading proposal suggested that KP1212 derived its mutagenicity by shape shifting–converting into a different molecular structure. The team also found that KP1212 could accept an extra proton, giving it a positive charge at physiological levels of acidity that made possible even more rearrangements. The experiments also showed that both the protonated and non-protonated forms facilitated the viral mutation rate. The team now believes that by decorating the KP1212 with groups of atoms and molecules that further raises their ability to capture protons they can create even more potent shape shifters. Experiments too, showed that many more such structures exist.
Usually most experimental tools have difficulty distinguishing between the normal and shape-shifted structures because they interconvert very rapidly. The UChicago team was able to distinguish between the two structures with 2D infrared spectroscopy and it will be a critical tool in their further work too.
The researchers say that KP1212 is on its way to being an ideal therapeutic mutagen. The new details of the stealthy workings of the anti-HIV agent KP1212 have been reported by Tokmakoff and his associates at UChicago and MIT last month in the Proceedings of the National Academy of Sciences.They believe that the spectroscopy will guide them toward even better mutagenic molecules.
