In a recent breakthrough in bioengineering, a team of experts gained inspiration from nature in revolutionizing pharmaceutical manufacturing. Their novel tool can be a game-changer in developing cleaner and more cost-effective drugs.
Need for More Effective Drugs
Most drugs bind to proteins in disease formation, blocking their activity to reduce the symptoms or treat the disease. Although this approach is practical, using conventional small molecules as drugs is not well suited to blocking interactions between proteins, which are pivotal in disease mechanisms.
In response, the pharmaceutical industry investigates the potential of peptides as the next frontier in medicine. These substances can mimic nature's molecules without posing challenges such as temperature sensitivity, fragile structures, and human cell infiltration.
However, peptides and proteins usually do not make very good drugs because their 3D structures can unwind due to sensitivity to high temperatures. They can also find it hard to get inside the body's cells where challenging drug targets are located.
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Harnessing 'Flower Power'
The challenge in harnessing peptides and proteins as drug candidates is their structural vulnerability. These molecules are not only sensitive to high temperatures, but they also tend to unravel. In addition, they often find it challenging to penetrate cells where many significant drug targets reside.
To address this problem, experts at the University of Bath attempted to improve the heat and chemical stability of proteins and peptides and make it easier for them to get into cells. Since proteins and peptide strands have a start and an end, they explored the possibility of joining these loose ends to create a very rigid "cyclic" connection.
In the study "Intracellular Application of an Asparaginyl Endopeptidase for Producing Recombinant Head-to-Tail Cyclic Proteins," the researchers took an enzyme called OaAEP1 from Oldenlandia affinis, a tropical plant with small purple flowers. They modified the plant before transferring it into bacterial cells grown to mass-produce a protein while joining the ends in a single step.
Generally, proteins and peptides are quite sensitive to heat, but cyclization makes these biomolecules more robust. The Oldenlandia plant makes cyclic proteins naturally as part of a defense mechanism to ward off predators, but it is slow and low-yielding. Meanwhile, cyclization can be carried out chemically by isolating the enzyme and combining multiple reagents in a test tube, although it requires several steps and uses toxic solvent chemicals.
When applied to a bacterial system, this process demonstrates positive effects such as increased yield, the use of more biologically friendly reagents, and the need for fewer steps. Therefore, this technology is much simpler and cheaper than the conventional process.
To test the effectiveness of this new approach, the research team applied their bacterial OaAEP1 technology to a protein called DHFR. It was found that joining its head and tail ends makes the molecule more resistant to temperature changes while retaining its normal function.
The new process has the potential for a wide range of applications, not only in the pharmaceutical industry but also in biotechnology, the food industry, the detergent industry, and bioenergy production.
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