Opening doors with drug design

Historically, the discovery of new medicines was a process based on trial and error. Small molecules, made from a mostly carbon skeleton, were tested on dishes of cells grown in the lab. This process would be repeated over and over again until scientists observed something interesting.

In the mid 1940s two scientists started to think about drug discovery in a different way. Dr George Hitchings hired Gertude Elion – a recent masters graduate – to join his team at the Burroughs-Wellcome pharmaceutical research laboratory (now GlaxoSmithKline) in New York.

It was the start of a lifelong scientific collaboration.

It’s only rational

Rather than relying on luck, Hitchings and Elion decided to synthesise new drugs with specific structures that were designed to interact with known targets in the body. This approach is now called rational drug discovery and has proven to be very effective.

Hitchings and Elion first designed compounds that could perturb the synthesis of nucleic acids, the molecules responsible for our genetic information. By looking at differences in the metabolism of nucleic acids in healthy cells compared to cells infected with cancer or other diseases, they designed drugs that could selectively block the growth of diseased cells.

Elion’s first task was to look at some of the molecules that make up our DNA – the purines. She made molecules in the lab that were subtly different to the natural purines, adenine and guanine. When tested in leukemia cells, the synthetic compounds were mistaken for their natural counterparts, preventing cell growth.

Elion and Hitching had discovered a new way of increasing the life expectancy of leukemia patients. But the drugs were too toxic and Elion was determined to find a cure. Her dedicated synthesis of over 100 analogues led her to discover new synthetic structures that could be used in combination with other drugs to cure most leukemia patients.

In 1988, Elion and Hitchings shared the Nobel Prize in Physiology or Medicine with Sir James Black ‘for their discoveries of important principles for drug treatment’. In addition to leukemia treatments, Elion and Hitchings had successes in many other disease areas including the development of medicines essential for organ transplantation, malaria, bacterial infections and gout.

When Hitchings retired, Elion became Head of Department and returned to the study of purines – but this time to look at their antiviral activity. She discovered a molecule that could disrupt the herpes virus, leading to the discovery of the cold sore medicine acyclovir and later to the development of the AIDs medication AZT by her colleagues.

Irrational Discrimination

Elion’s exceptional contribution to science is indisputable, but it was far from inevitable. A bright young woman, she graduated with the highest honours from her chemistry degree but was unable to obtain a scholarship to attend graduate school.

“I hadn’t been aware that any doors were closed to me until I started knocking on them,” Elion later remarked.

After saving the money she needed for further study, Elion completed her Masters in Chemistry and graduated as the only woman in her class in 1941.

Luckily for the many patients who have benefited from her work, Elion kept knocking on doors until someone let her in.

Dr Alice Williamson’s Breaking Good team recreated one of Gertrude Elion’s inventions, the malaria and toxoplasmosis drug Daraprim, following a price-hike in 2015.