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Aptamers as protein-protein interaction inhibitors

Protein-protein interactions were once considered undruggable. Our tailored aptamer selection approach is proving this isn’t so.

Targets such as transcription factors, immune checkpoints in oncology, infectious disease agents, and inflammatory cascades all rely on protein-protein interactions (PPIs). With an estimated 650,000 protein-protein interactions compared to only ~20,000 protein-coding genes, there is huge scope to affect biological processes for therapeutic development and as part of research by inhibiting these interactions.

PPI inhibitors block the interaction between the two proteins to prevent cellular signalling pathways and affect function. But developing PPI inhibitors has been a challenge for researchers and therapeutic developers.

Why are PPIs hard to drug?

Many PPI surfaces consist of large flat interfacial areas as much as 4-6 times bigger than traditional inhibitory targets like enzyme active sites. The lack of structural elements in large, flat epitopes makes it difficult to target using specific antibodies, peptides or aptamers.

A further disadvantage of antibodies is their instability within the cytosol due to critical disulphide bonds in their structures. As aptamer structures do not contain disulphide bonds, they are functional within the intracellular environment. They can cross the cell membrane via pinocytosis and receptor-membrane endocytosis mechanisms to easily access intracellular targets. As they offer the specificity of antibodies but with cytosolic compatibility, this makes them good candidates for PPI inhibitors. This leaves the question of how to target aptamers for PPI inhibition.

Strategies for PPI inhibition with aptamers

The two major approaches to PPI inhibitors are competitive and allosteric inhibitors.

  1. Newer research has shown hot spots within PPI surfaces. The hot spots account for large proportions of the interaction energy, so targeting these spots within the PPI surface allows the creation of competitive PPI inhibitors. For aptamer development, this means targeting the specific surface site. Aptamers that bind specifically at the PPI site can block the interaction to prevent downstream signaling.
  2. Modulating the PPI surface through allosteric binding involves aptamer binding at a distal site on the protein, causing structural changes to the PPI surface that prevent the two proteins from binding.

If knowledge of allosteric sites upon protein targets is available, aptamer selection can be targeted to the allosteric site for the generation of allosteric PPI inhibitors. Otherwise, competitive PPI inhibitors would be the option, with the inclusion of both interacting proteins in the selection and confirmation of the PPI inhibition downstream.

PPI inhibitory aptamers prevent HSV-2 infectivity

Our Optimer platform has generated optimized aptamers to HSV-2 gD envelope protein to disrupt interaction with host cell entry receptors. Use of these Optimer binders in in vitro inhibited viral entry by ~90%.

(a) Optimer binders to HSV-2 gD envelope protein inhibit viral infectivity, (b) with a concentration-dependent response shown with specific Optimer binders.

For more information on our targeted discovery approaches download the application note or contact one of our team today.




#PPI#protein inhibitors#therapeuticaptamers

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