Each year, SCI’s Scotland group runs a competition where students are invited to write a short article describing how their PhD research relates to SCI’s strapline: where science meets business.
Katherine Macfarlane, a Pure and Applied Chemistry PhD student from the University of Strathclyde, was a runner up in this year’s competition. Her article ‘Bifunctional molecules - moving beyond biologics for global healthcare’ is reproduced here.
Bifunctional molecules - moving beyond biologics for global healthcare
Every year, across the globe, drugs worth billions of dollars reach their destination in an ineffective, or even actively harmful, state. Changes in environmental conditions such as temperature and moisture levels can chemically alter many drug formulations, which must therefore be transported in a carefully controlled manner. The necessary logistics can be highly complex and expensive and are apt to go awry. This can endanger the safety of patients, as well as having financial and reputational repercussions for drugs companies.
These logistical challenges are an increasingly high priority for the pharmaceutical industry, due to the rise of drugs known as biologics; large protein-based molecules produced in living biological systems. Conventionally, small molecule drugs are chemically synthesised and act by binding to a protein and inhibiting or activating its function to produce a positive outcome in the patient. However, most proteins lack accessible binding sites for such molecules. Biologics are able to direct biology in different ways, allowing them to target these “undruggable” proteins. They are especially successful in targeting extracellular proteins, which exist in solution outside cells, by binding to them and disrupting their biological functions. This can be exceedingly effective in treating cancer and autoimmune conditions, a fact reflected in the impact on the pharmaceutical industry: in 2018 biologics already accounted for over a quarter of total pharmaceutical sales, four of the top ten drugs being biologics targeting extracellular proteins.
This new class of drugs is not without its drawbacks: biologics are much more intensive to produce than small molecule drugs and, crucially, require rigorously temperature-controlled transportation to prevent them from denaturing. This is especially problematic with chronic conditions treated with biologics and for which a reliable long-term supply of medication is essential.
Pharmaceutical companies are increasing investment in their supply chains to address the new demand but are struggling to keep pace. The challenges are particularly acute in rural areas, the “last-mile” section of transportation being notoriously difficult to control and standardise. Distribution of biologics is therefore greatly limited in developing countries where the high cost of such treatments is already prohibitive. This restricts access to potentially life-altering treatments for patients suffering from cancer and autoimmune disease and naturally reduces the market potential of biologic drugs.
The limited accessibility of biologics has created a potent incentive to design small molecule alternatives, which are cheaper to produce and do not require temperature-controlled transportation. Bifunctional molecules, the focus of my research, are one potential candidate. They consist of two small molecules connected by a linker, allowing them to bind to two proteins at once. The proteins are brought in to close proximity, which can induce interactions between them. This constitutes a new way of directing biological processes, which can achieve similar therapeutic results to biologics. In my research, I synthesise and test experimental new bifunctional molecules known as ENDTACs, which target extracellular proteins by a different mechanism from their biologic counterparts. One end of the ENDTAC molecule binds to the target protein, the other to a particular type of internalising receptor protein on the surface of a cell. The receptor then takes the drug-protein complex inside the cell where it is destroyed, clearing the target protein from solution entirely. With ongoing research, it is my hope that this new scientific innovation will produce a new class of treatments with global reach. Through partnership between science and business, this new technology has the potential to impact both patients and the pharmaceutical industry as profoundly as the biologics which came before, while ensuring access for those living with disease across the world.