Thursday, February 13, 2014

Downsizing has major benefits

Published in Drug Discovery News

BRISBANE, Australia—After a decades-long search for a so-called “holy grail” of biochemistry, Australian researchers have announced they have found a way to significantly reduce the size of molecules that have similar bioactivity to large proteins, preserving the proteins’ functions while also making the new molecules far more stable in the body.
Scientists at the Institute for Molecular Bioscience at the University of Queensland have proved the concept and method of growing small, stable molecules around key amino acids in complement protein C3a, which helps reduce inflammation and fight disease. By focusing tightly on the bioactive area of the protein, they have reduced the size of the molecule from 77 amino acids to just three, making the product much more suitable for inclusion in medications.
C3a, like many proteins, is large and expensive to make, as well as quick to degrade once introduced into the body. But this technique not only makes the molecules cheaper and smaller, it also makes them far less susceptible than the full protein to enzyme breakdown or immunogenicity once in the bloodstream.
Prof. David Fairlie, who co-led the research group with Dr. Robert Reid, said the method should be generalizable to other proteins with very different functions. “This technique is not specific to C3a. It relies only on knowing the location of a single amino acid of a binding protein within its receptor protein,” he says. “The trick … is of course to first know the location of an amino acid within the biologically active region of that protein, and then to know what amino acids in the target protein that you wish to bind to.”
Making that connection possible involves a very complicated multistep process, which is laid out in an appendix to the journal article announcing the discovery, published in Nature Communications in November under the title “Downsizing a human inflammatory protein to a small molecule with equal potency and functionality.” Involving multiple chemicals, heat, stirring and other techniques to build up and rearrange the amino acids so they will fit with the target protein, the process must not only preserve the amino acids themselves, but also build up a molecular scaffold that mimics the shape of the original protein, to ensure proper binding. The method took about 20 years to perfect, including the last 10 years focusing specifically on C3a as an example, Fairlie notes.
The breakthrough makes possible new and more effective medications more specifically targeting proteins in the body. Because the method of making smaller molecules is not specific to C3a, “it is potentially applicable to any protein involved in any disease, and most diseases involve proteins interacting with other proteins or macromolecules,” Fairlie says.
The lab will continue to work to improve “small-molecule drugs that target the human complement C3a receptor for use in treating inflammatory and metabolic diseases,” Fairlie says. And the researchers will use the now-proven approach to work with other types of proteins, targeting “a wide range of diseases like viral and parasitic infections, inflammatory diseases such as arthritis, metabolic diseases such as obesity, type 2 diabetes and cardiovascular disease and cancers,” according to Fairlie.
Beyond protecting the intellectual property with patent applications, the lab is “interested in discussing license agreements with pharmaceutical and biotechnology companies,” says Mark Ashton, manager for innovation and commercial development at Uniquest, the University of Queensland’s main commercialization company.
To that end, the lab has established a partnership with Pfizer, including $2.2 million in funding from the Australian Research Council and another $2.1 million from Pfizer itself, to develop specific new medicines with this technique. This may result in some medications that can be delivered orally using smaller drugs, where “currently there are only large peptide drugs available that need to be administered intravenously,” Ashton said.