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A team of scientists at the Weizmann Institute of Science, working in collaboration with scientists at St. Jude’s Children’s Research Hospital in Memphis, Tennessee, has shown exactly why a new drug that’s been proven effective against colon cancer has sometimes serious side effects. Their hope is that these findings will allow the drug’s design to be improved so as to lower the incidence of these side effects.
CPT-11, which has recently been approved for use against colon cancer, is really a prodrug; meaning it must undergo a change in the body to work. The active drug molecule is packaged in a longer molecule that helps keep the drug stable when injected. Inside the body, a naturally occurring enzyme interacts with the prodrug, snipping off a part of the molecule to release a potent anti-cancer treatment.
The side effects, which include nausea, vomiting and diarrhea, seemed similar to those experienced by some users of Alzheimer’s drugs; leading scientists to suspect that a second enzyme with a similar structure that is targeted by the Alzheimer’s treatment might be involved. Weizmann Institute scientists Prof. Joel Sussman and Dr. Michal Harel of the Structural Biology Department and Prof. Israel Silman of the Neurobiology Department have been studying this enzyme, acetylcholinesterase (AChE), and its mode of operation for many years, and decided to work with the Dr. Phil Potter and his team of St. Jude researchers to find out how it comes into play during cancer therapy.
The scientists soaked crystals of AChE with a solution of CPT-11, obtaining crystals of the complex of the two. Bouncing powerful X-rays off the protein crystals yielded a three-dimensional image of the dual protein structure, showing them exactly how the prodrug and the enzyme interact.
Comparing the structure of the CPT-11/AChE complex with computer-generated models of the enzymes that convert the drug, they found the cause of the problem to be a physical misfit. In all the enzymes, the CPT-11 molecule must enter a narrow cavity or gorge in the enzyme structure. While the prodrug is indeed cleaved by an active site near the bottom of the drug-converting enzymes’ gorge, in AChE it is trapped in such a way that the active site can’t cleave it. Instead, the prodrug blocks the enzyme like a cork, rendering it useless.
“The enzymes are like locks made by the same locksmith, but varied slightly to open with different keys. The cancer drug fits AChE like a key that slides in part way, but won’t turn,” says Sussman.
“As far as we know, this is the first time the side effect of a drug has been observed at the atomic level.” Drug designers may now be able to tweak the shape of the AChE-blocking segment of the prodrug molecule (which gets left behind in any case). The study may also have implications for the design of new Alzheimer’s drugs.
Prof. Joel Sussman’s research is supported by the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly; the Joseph and Ceil Mazer Center for Structural Biology; the Charles A. Dana Foundation; the Divadol Foundation; the Jean and Jula Goldwurm Memorial Foundation; the late Sally Schnitzer, New York, NY.; the Kalman & Ida Wolens Foundation; and the Wolfson Family Charitable Trust. Prof. Sussman is the incumbent of the Morton and Gladys Pickman Chair in Structural Biology.
Prof. Israel Silman’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Charles A. Dana Foundation; the Divadol Foundation; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly; and the estate of Annie Zim, UK.