Bespoke polymers put SU start-up on map

Spotlight on membrane proteins

Membrane proteins make up approximately a third of the proteome (the total protein content encoded by the genome) of living cells. Many diseases commonly associated with mutations are linked to malfunctions of these proteins, underscoring their medical importance. 

“These proteins facilitate a range of biological processes such as the flow of molecules through and across membranes, responses to chemical messengers, and cell-to-cell communication within the human body,” Kuyler points out. “They function almost like ‘locks’ that only the right drug can open so as to access the cell and activate a response.”

The crucial role of membrane proteins in drug development is evident in the fact that they comprise such a large portion of all drug targets. But why, then, do we know so little about them?

“The problem lies in how difficult it is to isolate or remove membrane proteins from the cell membrane in order to study their structure and function in a biologically representative state,” Kuyler explains. 

The native environment (i.e., the cell membrane) in which membrane proteins are embedded consists of two layers of phospholipids — molecules that each have a hydrophilic head and two hydrophobic tails. Their unique structure enables them to form the foundation of biological membranes.

For the accurate design of new therapeutics, membrane proteins need to be extracted in their unaltered, stable, and fully functional form from the lipid environment that makes up the cell membrane.

“The difficulties arise from the amphiphilic nature of membrane proteins and the consequent need to extract them in a way that stabilises both the hydrophobic and hydrophilic parts. If this is not achieved, the protein can lose its true structure and function.

“Understanding these aspects of drug targets can not only reduce the time and cost of drug development but also holds the potential to enhance the efficacy of drugs, ultimately minimising side effects and reducing the cost thereof,” says Kuyler.

Isolating membrane proteins, innovatively

Generally, technologies in the field of polymer science are related to high-volume, low-value manufacturing that requires significant manufacturing capabilities.

“With the advent of the new polymer-stabilised nanodisc technology, much focus is placed on low-volume, high-value products with a specific application,” Kuyler explains.

The nanodisc technology opens up collaborative opportunities within the research community and in commercial partnerships.” She adds: “The advanced synthetic strategy that we employ is highly customisable, allowing for dedicated polymer design and various specialised application."

The term ‘nanodisc’ describes a disc-shaped particle, composed of phospholipids that are held together by a synthetic polymer belt. These tiny structures have dimensions as small as one-billionth of a metre (a nanometre) — invisible to the naked eye and most microscopes.

“Being able to operate at this scale enables us to understand and study the fundamental building blocks of materials and biological systems,” says Kuyler.  Barnard adds: “Research at the nanoscale empowers us to utilise the unique properties of materials and drive innovation in various applications.”

The discs make the difficult-to-study membrane proteins amenable to analyses previously restricted to soluble proteins only. This is because, in these nanoscale discs, the water-insoluble component of amphipathic polymers can interact with and destabilise the cell membrane to isolate and stabilise membrane proteins along with their surrounding lipids.

This technology, therefore, offers researchers the unprecedented opportunity to access some of the most valued proteins in a biologically active state.

The Nanosene researchers use polymer-based molecular ‘cookie cutters’ to isolate the complex membrane proteins and keep them embedded within the portion of the cell membrane, thus preserving its molecular structure in its near-original context and stable form.

The nanodisc serves as a snapshot of the native environment that the membrane proteins had in the cell membrane. This is because water-soluble amphipathic polymers (containing both water-repellant and water-loving components) can interact with and enter the cell membrane to isolate and stabilise intact and functioning membrane proteins, along with their surrounding lipids, in these discs.

In contrast to soluble proteins, the amphipathic properties of membrane proteins prevent solubilisation in a standard water-based solution as the hydrophobic parts of the proteins bundle together to minimise contact with the solution.

“Until not too long ago and even right now, membrane proteins are being isolated with detergents,” Klumperman points out. “This leads to poor stability of the proteins and associated problems in their downstream use, such as for drug development and drug screening.”

“This undeniably changes the structure and folding of the membrane protein, typically hindering studies of its native form,” Kuyler explains. “This problem can, however, be addressed by using synthetic polymers to form polymer-stabilised nanodiscs.”

Nanosene produces polymers that have predetermined molecular weights with narrow chain length distributions and the possibility of having their hydrophilic-hydrophobic balance precisely fine-tuned. “This breakthrough technology can outperform conventional detergent-based methods [of isolating protein membranes] and holds the potential to empower researchers and drug developers to explore new avenues for treating various diseases.”

Compared to other current materials, our material offers the possibility of introducing additional functionalities such as fluorescent labels, affinity tags, and tethered surfaces,” Klumperman explains in a recent video. Barnard adds: “We believe that by adopting our customised polymer solutions and substituting traditional techniques with our innovative methods will enhance the efficiency and effectiveness of identifying potential drug targets for new therapeutic development.”