A multi-center collaboration led by Imperial and UCL has demonstrated how a mysterious molecular concept that the authors referred to as ‘range selectivity’ could be the key to unlocking highly targeted drug therapies.
Researchers, within synthetic systems, are still striving to achieve the precise binding selectivity seen within nature. For example, antibodies can bind to particular epitopes with very high strengths. Yet, tiny molecular-level variations can make them completely ineffective. In many cases, binding occurs by the formation of multiple bonds between ligands and complementary receptors on the target (multivalent binding). This binding modality achieves highly selectivity. Over the last decade, so-called multivalent super-selectivity has emerged as a hot topic for the development of targeted drug delivery.
In this article, published in Nature Communications, researchers used a combination of theory, numerical modelling and experiments to present a qualitatively different type of selective targeting. This type arises in systems where attraction is dominated by the formation of ligand-receptor bonds. The team dubbed this phenomenon ‘range selectivity’. Range selectivity, a previously mysterious phenomenon, is where ligands only attach to cells whose number of receptors reach a certain threshold level.
Dr Stefano Angioletti-Uberti, senior author and principal investigator, stated:
“I came across the concept of range selectivity completely by accident. During my theoretical investigation of receptor-ligand binding I noticed that ligands weren’t attaching above a certain threshold of receptor density and had my team re-check our code before realising it wasn’t a bug.”
In nature, range selectivity occurs due to a balance of attractive and repulsive forces at the molecular level. After a certain threshold, the repulsive force must outweigh the attractive and so binding is less likely to occur.
The team used statistical modelling to demonstrate how modifying certain parameters could tune the balance of these forces. In turn, this provided a molecular handle to tune the upper and lower limit of the selectivity.
The team hope that by finding receptor densities that are specific to different disease, they could apply this approach and treat those diseases with fewer side effects. Alongside drug targeting, the researchers also believe that their findings provide insight into how tumours evade immune response.
Dr Angioletti-Uberti explained:
“Could it be that tumour cells’ receptor densities fall outside the range toward which immune cells are programmed to target?”
In order to implement their findings into targeted drug delivery, the team suggest that some fine tuning of the system is required. They suggest that for selective drug targeting, researchers could restrict binding to a relatively small range of receptor densities. The team are now looking into how they could optimise receptor density on cells to ensure maximum binding.
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