into print.
“It’s a contradiction,” Ted Fox explains. “You want to have your protein in a nice soluble, water-based environment, and then you’ve got these peptides that are happy only in organic solvents. They don’t want to be in water. Different solvents, different buffers. It’s a constant game: Can you feed a little bit of it into the protein? Then again, once you’ve got it inside the protein with the protein wrapped around it, occupying its natural spot, it’s fine. A lot of it is fortuitous.”
During the summer, the company grew its first diffraction-grade crystals of HCV protease—three years and many millions of dollars since Peattie flew to Saint Louis to meet with Rice. The X-ray structure emerged within weeks, and in a frantic push to get it out the door, Murcko, Thomson, Caron, crystallographer J. L. Kim, and numerous others worked around the clock to submit the paper to the journal Cell , which published it in October. To the extreme disappointment of some of them and the disbelief of all, they were not alone. Agouron, which also had a structure of the protease domain in press—though without the cofactor—was claiming a tie, even though its enzyme showed no meaningful activity.
Boger normally avoided public disputes over scientific priority—it was more important to him that information be found and available than who discovered it—but a statement by an Agouron scientist about catching Vertex at the finish line rankled him, and he responded with an incendiary fax. “ ‘First of all,’ I said, ‘This isn’t the finish line. And second of all, your protein is dead ,’ ” he recalls. “I was outraged that they were projecting to the gullible scientific press that they had anything. They couldn’t use it for anything. It was inactive.”
Yet if Vertex once again had come from behind and bolted ahead of the competition, it was not at all clear from the crystal structure itselfwhat it had won. Caron’s model proved to be spot-on. The binding pocket of the protease was large, smooth, exposed, and greasy—nothing, apparently, like the cozy nooks of HIV and ICE. As the scientists examined it on their computer screens and started talking among themselves about how hard it would be to design inhibitors to block it, a few preferred metaphors arose: a dinner plate; an aircraft carrier; like trying to land a model airplane on a pizza.
“This protein,” Boger observed drily, “was just not well behaved.”
CHAPTER 3
----
APRIL 11, 1997
The hepatitis C virus offered other inviting targets: a motor enzyme called a helicase that can unzip spirals of genetic code, and a polymerase, which spools out new strands of DNA. At Schering-Plough Corporation, an industry leader in structural biology, virologist Ann Kwong had done vital work to characterize the helicase. But Kwong was frustrated, quietly seeking another job. She had come to Schering’s New Jersey labs from a postdoc at Memorial Sloan-Kettering Cancer Center, where she’d shown a Thomson-like fortitude working day and night in a windowless cold-room. The company, best known for its blockbuster antihistamine Claritin, sold the first approved drug for hepatitis C, Intron A, a biologic, and it was heavily invested in and publicly committed to using structure-based design against HCV.
Kwong doubted the effort was working and had begun to challenge her bosses in meetings. Now she took the podium to give a plenary lecture on hepatitis C drug discovery at the Tenth International Conference on Antiviral Research in Atlanta. Tung and Thomson, representing Vertex, listened with special interest, then moved swiftly when a couple of members of Kwong’s group mentioned afterward that she was considering offers from other companies. Vertex had so far resisted setting up disease groups because it was organized around protein targets, not illnesses. But Sato was impatient with the pace of discovery in HCV, and the company desperately needed
“It’s a contradiction,” Ted Fox explains. “You want to have your protein in a nice soluble, water-based environment, and then you’ve got these peptides that are happy only in organic solvents. They don’t want to be in water. Different solvents, different buffers. It’s a constant game: Can you feed a little bit of it into the protein? Then again, once you’ve got it inside the protein with the protein wrapped around it, occupying its natural spot, it’s fine. A lot of it is fortuitous.”
During the summer, the company grew its first diffraction-grade crystals of HCV protease—three years and many millions of dollars since Peattie flew to Saint Louis to meet with Rice. The X-ray structure emerged within weeks, and in a frantic push to get it out the door, Murcko, Thomson, Caron, crystallographer J. L. Kim, and numerous others worked around the clock to submit the paper to the journal Cell , which published it in October. To the extreme disappointment of some of them and the disbelief of all, they were not alone. Agouron, which also had a structure of the protease domain in press—though without the cofactor—was claiming a tie, even though its enzyme showed no meaningful activity.
Boger normally avoided public disputes over scientific priority—it was more important to him that information be found and available than who discovered it—but a statement by an Agouron scientist about catching Vertex at the finish line rankled him, and he responded with an incendiary fax. “ ‘First of all,’ I said, ‘This isn’t the finish line. And second of all, your protein is dead ,’ ” he recalls. “I was outraged that they were projecting to the gullible scientific press that they had anything. They couldn’t use it for anything. It was inactive.”
Yet if Vertex once again had come from behind and bolted ahead of the competition, it was not at all clear from the crystal structure itselfwhat it had won. Caron’s model proved to be spot-on. The binding pocket of the protease was large, smooth, exposed, and greasy—nothing, apparently, like the cozy nooks of HIV and ICE. As the scientists examined it on their computer screens and started talking among themselves about how hard it would be to design inhibitors to block it, a few preferred metaphors arose: a dinner plate; an aircraft carrier; like trying to land a model airplane on a pizza.
“This protein,” Boger observed drily, “was just not well behaved.”
CHAPTER 3
----
APRIL 11, 1997
The hepatitis C virus offered other inviting targets: a motor enzyme called a helicase that can unzip spirals of genetic code, and a polymerase, which spools out new strands of DNA. At Schering-Plough Corporation, an industry leader in structural biology, virologist Ann Kwong had done vital work to characterize the helicase. But Kwong was frustrated, quietly seeking another job. She had come to Schering’s New Jersey labs from a postdoc at Memorial Sloan-Kettering Cancer Center, where she’d shown a Thomson-like fortitude working day and night in a windowless cold-room. The company, best known for its blockbuster antihistamine Claritin, sold the first approved drug for hepatitis C, Intron A, a biologic, and it was heavily invested in and publicly committed to using structure-based design against HCV.
Kwong doubted the effort was working and had begun to challenge her bosses in meetings. Now she took the podium to give a plenary lecture on hepatitis C drug discovery at the Tenth International Conference on Antiviral Research in Atlanta. Tung and Thomson, representing Vertex, listened with special interest, then moved swiftly when a couple of members of Kwong’s group mentioned afterward that she was considering offers from other companies. Vertex had so far resisted setting up disease groups because it was organized around protein targets, not illnesses. But Sato was impatient with the pace of discovery in HCV, and the company desperately needed
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