When they made their potentially life-saving discovery, Dr. Lakshmi Kotra and his colleagues were engaged in pure research. “We started this in 2001 as an academic project,” Dr. Kotra explains from his lab in the east tower of Toronto’s MaRS research complex. “We were curious to understand a mechanism.”

The mechanism in question was the operation of an enzyme with a name so unpronounceable that scientists usually refer to it simply as ODCase (pronounced “oh-dee-see-aze.”)

Enzymes are special proteins that enable and accelerate a wide range of biological processes. One example: turning the complex carbohydrates we eat into simple sugars that the body can “burn” for energy. Dr. Kotra and his team were interested in ODCase because it’s one of nature’s most potent enzymes, rapidly accelerating the transformation of orotate monophosphate into a substance called uridine monophosphate—essential in the duplication of DNA and RNA.

In the world of enzymes—and indeed all proteins—shape is everything. An enzyme can operate only on a target substance whose molecules have a complementary three-dimensional form, like a key fitting a lock. Dr. Kotra’s team was using sophisticated equipment—funded in part by the Ontario Innovation Trust—that allowed them to visualize the molecular shape of the enzyme and to design custom compounds whose molecules “fit into” its surface.

One particularly interesting compound—KP-15—had the effect of inhibiting the enzyme altogether. “At first we thought we’d just get a good paper out of it,” says Dr. Kotra. But in one of those breakthrough moments that can transform pure research into a life-saving application, the scientists came across evidence that pointed to ODCase as an essential enzyme in the survival and development of the parasite that causes malaria.

“We hooked up with a clinician-scientist, Dr. Kevin Kain,” says Dr. Kotra. “He tested the compound against malaria, even drug resistant strains, and voila: we found something that is very potent.” Preliminary testing of a drug based on the compound has already started, although human trials are still a few years away. In the mean time, the team is exploring other potential implications of the compound in the treatment of cancer and other infections.



On another front, Dr. Kotra’s fifth-floor lab is custom-designing molecules that may one day lead to a form of insulin that diabetics can take orally. Like the work on ODCase, it offers the potential of another
life-saving application from the not-so-ivory tower of advanced biomedical research.