A cure for sleeping sickness?

Tse tse flies carry the t. brucei par­a­site respon­sible for African sleeping sick­ness. Photo via Flickr.

A few years ago chem­istry and chem­ical biology pro­fessor Mike Pol­lastri met a researcher name Larry Ruben at a con­fer­ence. Ruben was pre­senting a poster on an enzyme that is impor­tant to the sur­vival try­panosoma brucei, the cul­prit par­a­site in the neglected trop­ical dis­ease known as African sleeping sick­ness, or human African trypanosomiasis.

The poster was par­tic­u­larly exciting to Pol­lastri, who had recently left the phar­ma­ceu­tical industry to forge a research career in acad­emia, where the eco­nomic con­straints of big pharma wouldn’t pre­vent him from pur­suing cures for neglected dis­eases, which offer little in the way of profit.

The enzyme Ruben pre­sented is in a class called Aurora kinases, some of which are impor­tant to cell sig­naling and growth. From his back­ground, Pol­lastri knew that there are sev­eral drug com­pounds designed to inhibit human Aurora Kinases. For example, Danusertib, a drug cur­rently in phase II clin­ical trials, inhibits the human enzyme, pre­venting the unchecked cell growth seen in cancer.

Pol­lastri and Ruben began by testing a handful of human drug com­pounds for their ability to inhibit the t. brucei enzyme. At the time, Pol­lastri was still teaching at Boston Uni­ver­sity but when he came to North­eastern he joined forces with pro­fessor Mary Jo Ondrechen, whose exper­tise is in chem­ical mod­eling. Together, the two labs came up with a long list of Danusertib analogs to test. A recent article in the Euro­pean Journal of Med­i­c­inal Chem­istry presents their results.

A stu­dent in Ondrechen’s lab, now Dr. Zhouxi Wang, “per­formed the cal­cu­la­tions to help to pri­or­i­tize com­pounds for syn­thesis — pre­dicting which com­pounds are most likely to bind to the parasite’s kinase,” said Ondrechen. To reduce the chances of side effects, the team looked at com­pounds that bind to the par­a­site pref­er­en­tially over the human kinase, she said.

The ratio­nale for starting with pre-​​existing drug com­pounds is mul­ti­fold. On the one hand, it gives the team a rational starting point. But it also addresses these issues of tox­i­city and side effects from the beginning.

We could run a high throughput screen, wade through a mil­lion com­pounds to find these things,” said Pol­lastri. “But then we’d have to learn about how that chem­ical behaves in the bio­log­ical system all over again.” On the other hand, if they already know how a class of chem­i­cals behaves in the body, then they can use that infor­ma­tion to direct more effi­cient clin­ical trials.

After get­ting the data from Ondrechen’s team, Stefan Ochiana form Pollastri’s team syn­the­sized a couple dozen of them. In some cases, the com­pounds were nearly 25 times better at inhibiting the t. brucei enzyme than the human enzyme. They are cur­rently not quite as potent as Danusertib, but they have chem­ical struc­ture expla­na­tions, which they believe they can tweak to improve both the selec­tivity and the potency of the poten­tial drugs.