Janet Rideout is an organic chemist and one of the scientists who discovered that azidothymidine (AZT) could be used as an antiretroviral agent to treat Human Immunodeficiency Virus (HIV). She also played a key role in the development of acyclovir, the first effective treatment for herpes simplex virus.
Early life and education
Janet Rideout was born Janet Litster January 6, 1939, in Bennington, Vermont. She received bachelor's and master's degrees in chemistry from Mount Holyoke College. She then earned a PhD in organic chemistry from State University of New York, Buffalo in 1968.
Research and career
Shortly before graduation from the State University of New York, Buffalo, Rideout was hired by chemist and future Nobel laureate Gertrude Elion to work at a small US subsidiary of the British pharmaceutical company Burroughs Wellcome Company (now GlaxoSmithKline). Initially located in Tuckahoe (village), New York, the branch moved to Research Triangle, North Carolina, in 1970.
Rideout specialized in nucleoside chemistry. Nucelosides are chemical compounds consisting of a pentose sugar bound to a nitrogenous base. When phosphorylated, nucleosides become nucleotides, which are the building blocks of nucleic acids (DNA and RNA). As such, they're needed for replication (copying of the genome before cells divide so that each gets a copy). Therefore, cells that replicate frequently, such as cancer cells and bacteria have a high demand for nucleosides. Recognizing this, teams of scientists, including a team at Burroughs Wellcome including Janet Rideout dedicated themselves to studying chemical analogs that could mimic natural nucleosides, inhibiting replication.
Arabinosides
One branch of Rideout's research involved the synthesis of purine arabinosides (similar in structure to the canonical nucleosides found in DNA and RNA, but containing the sugar arabinose instead of ribose or deoxyribose). Rideout synthesized the nucleoside analog diaminopurine arabinoside, which was found to be active against herpes simplex virus and vaccinia virus and with a lower toxicity than similar compounds. In her Nobel lecture, Gertrude Elion credits this finding with initiating her group's "antiviral odyssey," which would lead to the development of the HIV treatment AZT, the herpes treatment acyclovir, and other important antiretroviral compounds.
The promising results from diaminopurine arabinoside led Rideout to synthesize additional purine arabinosides, in hopes of developing more effective antivirals. She worked with a team including virologists J. Bauer and P. Collins to study their pharmacological properties, discovering that aminopurine arabinosides had antiviral activity that was dependent on their amino group. This knowledge helped lead to the design of more potent antiviral medications including acyclovir, the first active selective drug against herpes viruses.
AZT
Rideout also studied nucleosides' antibacterial properties. One of the compounds that interested her was azidothymidine (AZT), identical to the canonical nucleoside thymidine found in DNA except for the 3' position, where AZT has an azide (N3) group instead of a hydroxyl (OH) group. That 3' OH is needed for linking nucleotides together, so AZT could potentially act as a chain terminator (it could be added to a growing nucleic acid chain, but additional nucleotides couldn't link to it).
AZT was first synthesized in 1964 by a Michigan Cancer Foundation researcher, Jerome Horwitz, with hopes it could be used to treat leukemia, but it wasn't found to be effective and raised toxicity concerns so it was abandoned. There was limited research on it in the following years, including a report from a laboratory in showing it had activity against Friend virus, a murine virus that causes leukemia in mice, but retroviruses weren't thought to affect humans, and the paper drew little attention.
Rideout was interested in AZT's other potential applications; she studied AZT as an antibacterial agent at the Burroughs Wellcome Company for several years. The compound was particularly effective against gram-negative bacteria. In addition to chemical characterization and optimization of its synthesis, their research included pharmacokinetic and safety testing in rats. This experience, and the data they collected showing that the drug was tolerated in rats placed them in a prime position to expedite the drug development process.