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Stapling Peptides Could Spur Development of Cancer Drugs
The discovery could help speed the development of peptide-based drugs against diseases including cancer. Scientists say the methods they pioneered are simpler than existing techniques, one of which employs an expensive ruthenium catalyst to connect chemical side chains that protrude from the main body of helical peptides.
"There's a lot of potential here. Our chemistry is unique," said Qing Lin, assistant professor of chemistry who led the research. "There are not that many new drug targets out there today, which partly explains the declining number of FDA-approved new drugs in recent years. So there is a need to come up with new technologies that can overcome this barrier. To this end, stapled peptides could open a whole host of new targets for therapies."
Stapled peptides work as treatments against disease by binding tightly to target proteins within cells, thus disrupting specific protein-protein interactions that regulate many biological processes, including response to stress, signalling within cells, and cell death.
In their native state, peptides -- short strings of amino acids -- shift between different shapes, including a helix, sheet and random coil. Stapling the peptides' side chains encourages the peptides to adopt and stay in a helix, which enables them to enter cells more easily. The helical conformation also makes it more difficult for enzymes to break the peptides down, Lin said.
"Photoclick stapling," the first approach, involves synthesizing peptides that have alkenes in one side chain and tetrazoles in another. Under ultraviolet light, the two side chains form chemical bonds with one another.
The second stapling technique Lin and his colleagues devised requires the synthesis of peptides carrying a pair of amino acids called cysteines that contain sulfur in their side chains. When scientists expose these peptides to a chemical that reacts selectively with the sulfur atoms, the chemical forms a "staple" that connects the two cysteine side chains.
Experts believe stapled peptides could treat a wide variety of health problems, including cancer and inflammatory, metabolic and infectious diseases. "The field is large enough for multiple players," Lin said. "Stapling is a technology that many people believe will create a new class of drug therapies, hitting new targets that other therapies can't. Our chemistry is distinct from what's already out there."
MEDICA.de; Source: University at Buffalo