Dana Klug

Graduate researcher wins fellowship to design drugs to combat deadly disease

by Thea Singer

When North­eastern grad­uate stu­dent Dana Klug learned, in mid-​​July, that she had won a pres­ti­gious pre­doc­toral fel­low­ship from the Amer­ican Chem­ical Society Divi­sion of Med­i­c­inal Chem­istry, she did what researchers in labs around the world do on such occasions.

She hit “high elbows” with her advisor, asso­ciate pro­fessor of chem­istry and chem­ical biology Michael Pol­lastri, who heads Northeastern’s Lab­o­ra­tory for Neglected Dis­ease Drug Dis­covery.

You have gloves on,” Klug explains, laughing, “so you bump elbows instead of doing a high five.”

In Klug’s case, those gloved hands had spent count­less hours manip­u­lating chem­ical compounds—small mol­e­cules that Pollastri’s lab had iden­ti­fied as pos­sible drug can­di­dates to treat Human African try­panoso­mi­asis, or sleeping sick­ness, a deadly dis­ease trans­mitted by tsetse flies that affects tens of thou­sands of people in rural Africa annually.

The $26,000 fel­low­ship, given to grad­uate stu­dents in their third or fourth year of study, will enable Klug to con­tinue designing and syn­the­sizing vari­a­tions of 16 of those com­pounds in the coming year in an effort to find the ones most effec­tive at killing the par­a­site that causes the disease.

Dana Klug

Photo by Matthew Modoono/​Northeastern University

This is a national award and is really com­pet­i­tive,” says Pol­lastri, who with his col­leagues in 2014 reported iden­ti­fying 797 com­pounds as “starting points” for dis­cov­ering new drugs for sleeping sick­ness after screening more than 42,000 com­pounds sup­plied by col­lab­o­rator Glax­o­SmithK­line, the global health­care company.

Klug’s 16 com­pounds, broken into two groups with sim­ilar chem­ical struc­tures, come from those 797. “Stu­dents in the top med­i­c­inal chem­istry research groups in the country apply to this pro­gram, and only three received the award this year,” says Pol­lastri. “It’s a strong state­ment about Dana’s promise as a future leader in the field.”

Klug’s interest in neglected trop­ical dis­eases such as sleeping sick­ness was sparked as an under­grad­uate at DePaul Uni­ver­sity, in Chicago, where she majored in chem­istry and minored in biology and soci­ology, taking courses in global health. Her under­grad­uate research advisor, asso­ciate pro­fessor Caitlin Karver, had been a post­doc­toral fellow in Pollastri’s lab and rec­om­mended that she apply to North­eastern for her doc­toral studies. “How’s that for a small world?” says Pollastri.

Upon accep­tance into Northeastern’s chem­istry PhD pro­gram, Klug received a Col­lege of Sci­ence Dis­tin­guished Grad­uate Fel­low­ship, which allowed her to jump directly into research with Pollastri’s team in October 2013. She did so with alacrity: “She’s one of those stu­dents to whom you explain some­thing once or just vaguely and she takes that and runs with it inde­pen­dently,” says Pollastri.

In designing her com­pounds, Klug is like a chef crafting a gourmet dish, adding an atom of, say, hydrogen here, removing an atom of nitrogen there, or shifting an ele­ment left to right to trans­form the chem­ical struc­ture of the indi­vidual mol­e­cule. “Syn­thesis is all about making and breaking bonds between ele­ments,” she says. “Each reac­tion brings about a spe­cific struc­tural trans­for­ma­tion that results in a new com­pound, which is then puri­fied and used as the starting mate­rial for the next reac­tion in the synthesis.”

Dana Klug

Photo by Matthew Modoono/​Northeastern University

Klug sends each iter­a­tion off to the Spanish National Research Council, in Granada, Spain, where col­lab­o­rator Miguel Navarro and the Glax­o­SmithK­line team mix it with both the sleeping-​​sickness par­a­site, Try­panosoma brucei, and human cells to test for potency in the first case and tox­i­city in the second.

What hap­pens in those Petri dishes helps deter­mine Klug’s next step. The 797 com­pounds Pollastri’s lab ini­tially selected as “hits” against T. brucei work by inhibiting pro­teins called kinases, which are found in both humans and par­a­sites. The job of kinases is to add phos­phate groups—structures of oxygen and phosporous—to other pro­teins inside cells, spurring those pro­teins to facil­i­tate cell growth and divi­sion. “If you inhibit human kinases, you can stop cell growth,” says Klug. “We believe that same inhibitory action occurs in par­a­sites, killing them or blocking their ability to reproduce.”

The results in Spain pro­vide clues for new variations.

Knocking out T. brucei is a tall order, but one to which Klug is com­mitted. “The orig­inal hits have a pretty good pro­file so I’m working on scaling up one of them to pos­sibly test in an animal model,” she says. “But I also have many plans for a lot of dif­ferent com­pound vari­a­tions that I want to make.”

Originally published in news@Northeastern on August 31, 2015.

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