How to hijack natural destruction in cells: ‘We need to understand it through and through’
Destroying proteins from the Golgi apparatus of the cell in a controlled manner. That is the focus of chemist Marta Artola’s pioneering research. By developing a groundbreaking technology to target specific proteins in the Golgi, Artola aims to unlock new ways for drug development. For this ambitious project, Artola was awarded with an ERC Starting Grant of 1.5 million euros.
What does car repair have to do with drug development? ‘To fix a broken car, you need to fully understand how the engine works. Similarly, you need to understand the biology of health and disease when developing a drug,’ Marta Artola explains, assistant professor at Leiden Institute of Chemistry. For this new project, Artola aims to understand how proteins from the Golgi apparatus can be broken-down naturally, so that she can hijack this process rationally using chemistry.
Currently, there are no ways of specifically degrading proteins in the Golgi, a key protein-processing system within cells. ‘To develop a technology for this, we need to understand how we can hijack the transporters that can carry those proteins to the lysosome, where the cell naturally degrades them.’
Marking proteins for destruction
Artola’s proposal is inspired by a technique called targeted protein degradation (TPD). As the name implies, it uses specific molecules to target proteins for degradation. First introduced in 2001, the technique was initially limited to proteins in the nucleus and the cell’s fluid (cytoplasm). A few years ago, TPD was adapted to proteins outside of the cell. However, some cell compartments, including the Golgi apparatus, cannot yet be targeted by these existing methods.
That’s where Artola’s new project comes in. She has designed molecules that target Golgi transporters on the one hand, and the proteins intended for destruction on the other hand. Once the transporters bind, they direct the whole complex to the lysosome, where it is naturally broken down. This is a completely new approach to target Golgi proteins for degradation and provides new inroads to develop drugs for currently untreatable disease.
Sweet degradation
Artola has a special interest in glycobiology, which is all about sugar metabolism. That is why the project is called ‘Sweet degradation’. Within the Golgi, several enzymes can break down or add sugar bonds. Some of these enzymes are very difficult to inhibit, but play an important role in diseases such as cancer or rare metabolic disorders.
Artola tries to create new molecules that promote breaking-down of these enzymes in the Golgi apparatus. She hopes this might eventually help patients.
Disciplines crossover out of interest
Artola is eager to dive into the project. Her team has already synthesised the first linking molecules, and developed a method to test their binding to Golgi transporters. With the addition of three new PhD students and one postdoctoral researcher, these initial efforts will mark the beginning of their work.
‘It allows me to go where I believe I can make a difference.’
The project requires a multidisciplinary approach, Artola says. ‘For example, we need organic chemists to synthesise the molecules, and biochemists to study their effects in cells.’ From her own experience, she knows that different disciplines tend to crossover out of interest. ‘Often, the people who synthesise the molecules, are also curious about their therapeutic potential. That’s what led me from organic chemistry to the field of medical biochemistry.’
‘It's a turning point in my career,’ Artola concludes. ‘This grant provides the tools and freedom to explore and develop innovative ideas, even those that might seem too risky or unconventional. It allows us to forge new paths where I believe we can make a difference.’