Research Night: Parasites, Purines, and Pharmaceuticals with Dr. Back
Dr. Back of the Department of Chemistry is a synthetic organic chemist who develops methods for building molecules and creating new reactions. He was kind enough to tell us all about his critical work in a more biological context, pertaining to parasites and the development of pharmaceuticals to kill those parasites.
Dr. Back works with target compounds that display biological activity, such as a natural product discovered by Japanese scientists that came from a rotting pumpkin. This product shows potent antiviral activity and is nanomolar against both RNA and DNA viruses. However, the product is not present in high amounts in the mold of rotting pumpkins, so chemists like Dr. Back are tasked with synthesizing it. The product is highly toxic to the liver, so chemists aim to synthesize analogues of the product that are antiviral but not toxic to the liver so that they are suitable for humans to use.
In addition to this, Dr. Back works with protozoa, which are single-celled eukaryotes that are often parasitic. Protozoa build their DNA differently than mammals do: our DNA is made up of nucleotides that form nucleic acids, but protozoan DNA is made up of nucleosides that form nucleic acids. Not only are the building blocks of our DNA different from those of protozoa, but the mechanisms by which they are assembled are also different. Humans use enzymes to assemble the building blocks, but protozoa are unable to use enzymes this way. This means they must scavenge their nucleosides from the host they have infected. The nucleoside consists of a purine and a ribose sugar, and the protozoa cleave off the ribose sugar and salvage the purine, which they then rebuild to incorporate into their DNA. This phenomenon is a blessing to the scientists working with protozoa, as they are able to selectively interfere with the protozoan DNA but avoid interfering with the DNA of the host.
The purine that was cleaved from the ribose sugar is then synthetically modified by adding a fluorine or a chlorine to it. This purine gets sent to the Swiss Tropical Disease and Public Health Institute, where the Swiss may then work with it. They run assays against live protozoa, such as malaria, and if the compound kills the protozoa, the compound may then be tested on mammalian cells. The protozoa cleave the purine, with a chlorine or fluorine attached, from the ribose sugar it is attached to. The protozoa recognize the purine and start to incorporate it into their DNA. This is where things go downhill for the protozoa; the chlorine or fluorine attached to the purine ring is toxic to the protozoa, so the protozoa have just incorporated a toxic compound into their DNA. The protozoa end up undergoing programmed cell death by their own enzymes, which are called antimetabolites in this case. This process of altering the purine and providing the protozoa with it is an example of targeting a pathogenic infection.
However, there is one more hoop to jump through: the modified purine ring is also toxic to mammalian cells. Certain enzymes are used to phosphorylate a position on DNA so that the position may be filled, but chemists block that position to prevent it from being phosphorylated. This means the position is unable to be filled and therefore the modified purine will not move anywhere until it is about to be excreted, which means it will not be incorporated into DNA. This modified purine is 1000 times more toxic to a deadly strain of malaria than it is to a mammalian cell, an impressive feat for chemists. A similar success story has to do with leishmaniasis, where a modified compound has a selectivity index of 2700 for the leishmaniasis parasite. Mammalian cells have no response to the compound, but the leishmaniasis parasite dies when in contact with just nanomolar concentrations of the compound.
Drug development is a slow, painstaking process that is often frustrating as the benefits are often weighed against the profit margins and the demand for the drug. Unfortunately, many of the diseases that can be treated with drug development by scientists such as Dr. Back are prevalent in third world countries where people cannot afford to pay for them, so pharmaceutical companies are unwilling to fund further study and development. Not only this, but organizations must first successfully test their compounds with the target parasite, then with the target parasite along with mammalian cells, then with living tissue, and eventually with living organisms (animals). Despite these hurdles, Dr. Back is conducting very important work toward developing pharmaceuticals desperately needed in various places of the world.