Sarah Steele and Langtian "Ren" Yuan were both self-admittedly inexperienced Duke freshmen in the spring of 2006. But then they followed helpful directions of an assistant chemistry professor, added their own patience and ingenuity, and ended up identifying compounds that might allay the powerful cravings of methamphetamine and cocaine addiction.
The two women, now seniors, have since moved on to other things. But their earlier accomplishment was recently celebrated by a research paper in a British journal. It also helped bring the professor, Jiyong Hong, a $390,000 stimulus grant from the National Institutes of Health and the American Recovery and Investment Act to do follow-up research.
"I think this is a kind of showcase for something that Duke is very strong in -- undergraduate research," Hong said. "And, socioeconomically, it deals with drugs of abuse that are huge problems."
Hong, whose research group investigates the synthesis of natural products for drug design as well as small molecules' roles in biological processes, got interested in finding small molecules that could inhibit the good feelings induced by meth and coke after reading a 2006 paper in the journal Science.
That study implicated a derivative of an enzyme called protein kinase C zeta (abbreviated PKCzeta) in brain chemistry changes involved in memory and learning.
"When people take methamphetamines and cocaine, that gets engraved in their memories," Hong said. "So the hypothesis was that by inhibiting a specific enzyme, in this case PKCzeta, we might be able to delete those memories."
The problem was that researchers had never identified a PKCzeta inhibitor, he added. "PKCzeta is one of the least studied members of the PKC family." In other words, his quest would be like searching for needles in a haystack.
Enter the two undergraduates. Steele, an intended biology major, showed up in Hong's lab to do an independent study tied to a freshman chemistry research seminar class. "I hadn't taken organic chemistry, but he explained everything to me so I was sure of what I was doing," she said.
Following Hong's elaborate instructions, Steele began the task of canvassing about 1,200 different small molecules looking for candidate PKCzeta blockers. "It was repetitive work, but once we learned the concept it was easy to continue," she recalled.
The work involved placing each candidate inhibitor into one of 96 tiny wells on a sample plate, along with PKCzeta and an energy-providing chemical called adenosine triphosphate (ATP), plus a light-emitting enzyme called luciferase.
If a candidate compound was ineffectual, then the ATP in the well would be used by PKCzeta's activity. But if a compound did interfere with the PKCzeta, then the energy of the ATP would instead cause the luciferase to light up. The better the blocking action, the brighter the glow.