Scientists at the University of Bath have developed a new tool inspired by nature to help researchers develop new drug treatments in a cleaner, greener and more cost-effective way. Drug treatments often work by binding to proteins that play a role in the disease, thereby inhibiting their function. This procedure can relieve symptoms or directly treat the disease.
Traditional small molecule drugs often have difficulty disrupting interactions between proteins, and the pharmaceutical industry is exploring the use of small proteins called "peptides." These peptides work in similar ways, providing a potentially more effective way to block these interactions.
However, peptides and proteins often do not make good drugs because their three-dimensional structures can unravel, are sensitive to high temperatures, and have difficulty entering human cells, where many exciting but challenging drug targets exist.
Now, scientists at the University of Bath have developed a way around this problem: usually proteins and peptide chains have a start and end point - by joining these loose ends together, it is possible to create very stiff "ring-like" proteins and peptide chains, which improves heat resistance and chemical stability, and allows them to enter cells more easily.
They extracted an enzyme called OaAEP1 from Oldenlandia affinis, a small purple flower that grows in the tropics, modified it, and then transferred it into bacterial cells. These bacterial cultures can produce large amounts of protein as they grow, while connecting the two ends in just one step.
Plants can complete this process naturally, but it is slow and produces low yields. Alternatively, cyclization can be done chemically by isolating the enzyme and mixing multiple reagents in a test tube, but this requires multiple steps and uses toxic chemical solvents. Putting the entire process in a bacterial system increases yields, uses more sustainable biofriendly reagents, and requires fewer steps. Therefore, this method is simpler and cheaper.
To demonstrate this approach, the scientists applied bacterial OaAEP1 technology to a protein called DHFR and found that joining its head and tail ends together made it more resistant to temperature changes while still maintaining normal functionality.
Professor Jody Mason, from the Department of Life Sciences at the University of Bath, said: "Proteins and peptides are often quite sensitive to heat, but cyclization makes them stronger. Aldenlander plants naturally make ring-shaped proteins as part of a defense mechanism to deter predators. So we have harnessed the superpowers of this flower by engineering OaAEP1 and combining it with existing bacterial protein production technology to create a very powerful tool that will help the drug discovery industry."
Dr Simon Tang, associate researcher at the Department of Life Sciences at the University of Bath, said: "Proteins and peptides are very promising drug candidates, but an important bottleneck in developing new treatments is how to produce enough proteins and peptides for patients to use without incurring astronomical costs. I Our new process lets bacteria do all the work and is therefore cleaner and more environmentally friendly, with fewer steps and simpler operations. We are very excited about the potential applications of this technology, not only in the pharmaceutical industry, but also in other industries such as the food industry, detergent industry, biotechnology and bioenergy production."