Bioorthogonal Chemistry - Making Drugs Inside Patients - And More
That's one promise from an emerging new field of chemistry, according to the scientist who founded it barely a decade ago. Carolyn Bertozzi, Ph.D., spoke on the topic - bioorthogonal chemistry - delivering the latest Kavli Foundation Innovations in Chemistry Lecture at the 243rd National Meeting & Exposition of the American Chemical Society (ACS).
Bertozzi explained that the techniques of bioorthogonal chemistry may fundamentally change the nature of drug development and diagnosis of disease, so that the active ingredients for medicines and substances to image diseased tissue are produced inside patients.
"Suppose a drug doesn't reach diseased tissue in concentrations high enough to work," Bertozzi said, citing one example of the potential of the new chemistry. "Maybe it is an oral drug that doesn't get absorbed very well into the blood through the stomach. You can imagine a scenario in which doctors administer two parts of the molecule that makes up the drug. The two units reach diseased tissue in large amounts or get absorbed through the stomach just fine. Then they recombine, producing the actual drug in the patient's body. Bioorthogonal chemistry is chemistry for life...literally!"
Bertozzi explained that bioorthogonal chemistry opens the door to creating new proteins, fats and sugars directly inside living cells without harming them. The field emerged from her frustration in the late 1990s with the lack of tools available to see sugars on the surfaces of living cells. Chains of these sugars, called glycans, sit on the surfaces of cells in the body and control the doorways through which different molecules enter. When a disease-causing virus enters and infects a cell, for instance, proteins on the virus's surface attach to certain glycans.
"To do that, we had to come up with a chemical reaction that would be really selective, only targeting the sugar of interest and the fluorescent probes that we delivered to it," said Bertozzi. The chemicals also couldn't stick to other biomolecules that the researchers didn't want to see.
That turned out to be a tall order, indeed. "We pulled all of our big textbooks off the shelves and flipped through them to see if there was something out there that fit our criteria," she said. Those criteria were essentially the conditions inside a living cell or living organism such as a mouse - a reaction that could occur in water at pH 7 and at 98.6 degrees Fahrenheit. The reaction also couldn't interfere with all the other biomolecules in a cell or organism that keep it alive.
"It was a pretty restrictive set of conditions that a traditionally trained organic chemist like me never had to work within," she explained. That's because these types of reactions are usually performed in very clean, dry test tubes and flasks under conditions that the chemist can control. A living cell or organism, with all its water, proteins, fats, sugars and metabolites is very messy and uncontrollable by comparison.
Bertozzi and her team at the University of California, Berkeley, went on to develop a slew of reactions that can add fluorescent labels to biomolecules.
Now, the field is exploding, with her group and others reporting new bioorthogonal chemical reactions every year that help researchers see sugars, fats, proteins, and even DNA and RNA, that can't be seen using conventional methods. Researchers currently use the reactions not only to see where a biomolecule is within a living cell or organism, but also to determine when a biomolecule is made and what it binds to. Researchers also are using the methods to add things besides labels, like drugs, to various biomolecules. Some of the chemicals used for the reactions are currently available separately or in kits.
Several of Bertozzi's reactions are patented, and some are licensed to companies, including Redwood Bioscience, a company she co-founded with David Rabuka, Ph.D. The company is focused on bringing this technology to the clinic.
There has been a growing realization that the molecular details of biological processes can be most accurately understood by probing biomolecules within their native habitats - in cells and live organisms. In earlier decades, biology-derived technologies such as monoclonal antibodies and genetic fluorescent protein fusions enabled great strides toward elucidating the roles of specific proteins in dynamic cellular processes. Though their target selectivity is exquisite, these biological tools were not amenable to every protein type, and glycans, lipids, nucleic acids and metabolites were largely refractory to in vivo monitoring.
Consequently, chemists started contemplating whether target biomolecules could be rendered chemically unique within biological settings such that probe molecules might be delivered by the selective formation of covalent bonds. This was a maverick notion, given the obstacles that would be heaped upon the targeting reaction. To start with, the participating functional groups could not engage endogenous biological functionalities in competing side reactions. Moreover, the reaction would have to proceed rapidly in aqueous media, at biocompatible pH and temperature, and for applications involving live cells or organisms, the reagents should be nontoxic.
Only 12 years ago, there was not a single reaction that met all of these criteria, now recognized as defining attributes of bioorthogonal chemistry. In the last decade, the field has grown dramatically in regard to reaction development and applications in biological discovery. Bioorthogonal reactions of the azide, including the Staudinger ligation with phosphines and Cu-catalyzed or strain-promoted cycloaddition with alkynes were the first, and have been particularly influential in biology. The compendium continues to expand and now includes many new transformations that are already changing the ways biologists interrogate living systems. This presentation will focus on principles of bioorthogonal reaction development, highlighting work from my lab that seeks to apply the new brand of chemistry toward disease diagnostics.
The scientists acknowledged funding from the National Institutes of Health and the Howard Hughes Medical Institute.
Sponsored by The Kavli Foundation, a philanthropic organization that supports basic scientific research, the lectures are designed to address the urgent need for vigorous, "outside the box" thinking by scientists as they tackle the world's mounting challenges, including climate change, emerging diseases, and water and energy shortages.
"We are dedicated to advancing science for the benefit of humanity, promoting public understanding of scientific research and supporting scientists and their work," said Kavli Foundation President Robert W. Conn in a statement. "The Kavli Foundation Innovations in Chemistry Lecture program at the ACS national meetings fits perfectly with our commitment to support groundbreaking discovery and promote public understanding."
American Chemical Society
Source: EurekAlert!, the online, global news service operated by AAAS, the science society
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