Chameleon Peptides: Changing themselves or pharma?

Chameleons change colour by using specialized cells in their skin called chromatophores. These cells contain pigments such as melanin and carotenoids. By expanding or contracting the chromatophores, chameleons can change their colour. This means they can change how they look in response to the environment. In a similar fashion there are a class of molecules known as chameleon peptides that can change their properties in response to changes in their environment.

One of the biggest problems plaguing the cyclic peptide drug discovery efforts is getting the cyclic peptides to enter the cell so they can do their job. Once again nature has beaten us to the solution – chameleon peptides.

An example of a peptide chameleon is Cyclosporin A. It is an immune system suppressing drug which is critical to prevent the rejection of transplanted organs. It was was discovered in the early 1970s by a team of scientists at Sandoz, a Swiss pharmaceutical company (now Novartis). The discovery was made while the team was studying a soil sample from a Norwegian forest, which led to the isolation of a new type of fungus, named Tolypocladium inflatum. After several years of research and development, Sandoz launched Cyclosporin A, under the brand name Sandimmune, in 1983. It quickly became the standard of care for organ transplantation and it is still widely used today.

Cyclosporin is interesting because it is able to change its shape when in different environments. This is critical to it being able to successfully transverse the cell membrane. Getting through the cell is the achilles heel of many small peptides generated in the lab by phage display. As seen in the diagram below, cyclosporin can look inwards to satisfy it’s bonding requirements (the dotted lines) when it is in the middle of the cell membrane (a non-polar environment).

So active research is going into studying how cyclosporin transverses the cell membrane. Membrane-permeability studies have revealed that it is the chemicals ability to hide it’s polar groups when in the hydrophobic (non-polar) region of the cell membrane that allows it to get through. But it is the ability to flip back when it gets to the other side to show the polar groups. The solution we can copy for other drugs – flip inside out when inside the cell membrane and back again when outside of it. Evolutionarily this small ring peptide has been optimised to intermolecularly form hydrogen bonds when it is turned inside out. Thus giving it the cell penetrating peptide ability. The hope is by understanding chameleonicity we can convert great cyclic peptides into effective therapeutics.

Gone are the days of aiming solely for high affinity, selective, and enzymatic degradation stable cyclic peptides. Chameleon peptides might just offer the solution to also allow oral availability to be optimised. This is significant as it makes the biopharmaceutical realm more appealing to patients and investors alike.

Lipinski’s rule of 5 was created as a general rule of thumb to predict whether a drug would be able to be taken orally. In general it needs 5 H-bond donors, 10 H-bond acceptors, a molecular weight less then 500, and the calculated Log P (CLog P) is less than 5. However, the macrocyclic peptides such as Cyclosporin A clearly violate this rule yet exhibit oral availability. We refer to a compound that exists outside of this rule of 5 as beyond the rule of 5 (bRo5).

Another advantage of chameleon chemicals is that they can be larger then traditional small molecules. This is particularly useful because small molecule drugs are limited in there potential drug targets. For example, small molecules can’t block protein-protein interactions, whereas our larger cyclic peptides can! Chances are we will continue seeing more bRo5 compounds reaching the clinic, especially if science can find a way to make them chameleon peptides.

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We have already seen molecular chameleons reach the market, examples of these drugs include roxithromycin, telithromycin and spiramycin. Whilst these are non-peptidic and macrocyclic molecules, they are bRo5 compounds. They permeate through the cell by changing their shape, in turn changing their properties to suit the environment.

Virginia Woolf, wrote: “A self that goes on changing is a self that goes on living.” In the prose poem, The Waves (1931), perhaps we are seeing cyclic peptides following this notion. Through changing itself it can go on and enter the cell so it can go on to find its target.

In conclusion, macrocyclic peptides have already began revolutionising drug discovery. Finding a way to predictably make them cell-penetrating peptides will allow for more reliable and concerted efforts in the drug discovery realm. Replicating nature’s chameleon peptide solution to this problem might just be our best shot at pulling off the impossible.

Chameleon Peptide References

• Danelius, E., Poongavanam, V., Peintner, S., Wieske, L. H. E., Erdélyi, M., & Kihlberg, J. (2020). Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs. Chemistry – A European Journal, 26(23), 5231–5244. https://doi.org/10.1002/chem.201905599
  • https://pubmed.ncbi.nlm.nih.gov/32027758/
• Kim, B., Do, T. D., Hayden, E. Y., Teplow, D. B., Bowers, M. T., & Shea, J.-E. (2016). Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation. The Journal of Physical Chemistry B, 120(26), 5874–5883. https://doi.org/10.1021/acs.jpcb.6b00830
  • https://pubs.acs.org/doi/10.1021/acs.jpcb.6b00830
• Räder, A. F. B., Weinmüller, M., Reichart, F., Schumacher-Klinger, A., Merzbach, S., Gilon, C., Hoffman, A., & Kessler, H. (2018). Orally Active Peptides: Is There a Magic Bullet? Angewandte Chemie International Edition, 57(44), 14414–14438. https://doi.org/10.1002/anie.201807298
  • Read here: https://onlinelibrary.wiley.com/doi/10.1002/anie.201807298