The delivery of the next generation of therapeutic modalities into human tissues and cells is the next big hurdle in the race against disease progression. Some technologies have been used in an academic context for half a century but lacked specific breakthroughs to get them into the clinic. One of the key tools where this happened was Cell Penetrating Peptides.

With the identification of the HIV-1 TAT translocation sequence in the late 1980s, cell penetrating peptides (CPPs) were catapulted into the research landscape.^[1] With some initial successes, academic labs showed specific, short peptide sequences could enable small and large biologics alike to gain access to tissues and interact with intracellular targets. This enthusiasm grew upon the development of more robust and scalable methods to produce peptide sequences.^[2]

Initial theories as to a ‘general CPP mode of action’ focused on the increase of overall substrate charge giving greater penetrance, which was somewhat related to cell membrane potential. Further analysis showed a more complex balance between lipophilicity, charge, secondary structure and surface glycan interaction was at play.^[3] This started to mirror aspects of small molecule drug design with the Lipinski (Pfizer) rule of five being rewritten to fit a biologic drug context.   

However, CPP translation to clinically relevant drugs stalled when it became apparent that there were caveats to initial designs. After progressing through trials CPP-cargo conjugates were found to spend most of their circulation time trapped in endosomes, missing their intended site of action and producing no pharmacological benefit. Further to this, hepatotoxicity and CPP instability towards proteases started to dampen down the initial enthusiasm in the peptide related fields. This perpetuated for some time due to a reliance on noninnovative ‘natural’ substrates and a search for a ‘one-size fits all’ solution.

At the turn of the new millennium there was a concerted move away from this past paradigm, with ‘stapled’, ‘stitched’, ‘cyclic’ and peptoid technologies being developed using non-natural amino acid alternatives to better control physicochemical properties.   

TargoPep and Advanced Delivery Peptides (ADPs) grew from these positive beginnings and have actively addressed escape, stability and toxicity issues – using innovative medicinal chemistry and bespoke design principles. The core tuning of physicochemical properties provides the control required to safely access cellular space with high loading and escaping the endosomal entrapment pitfall.^[4]  

The drive for new and improved delivery techniques is not just the better understanding of ADPs which we now have, but  also the demands of a number of new and emerging therapeutic modalities: in particular gene-based therapeutics. These innovative therapies consistently give results on the bench which could provide curative routes for many chronic and debilitating disease states, but disappoint in the clinic by their lack of a method to deliver their active to the sites of activity. TargoPep’s focus is upon the next generation of gene-based therapeutics. These therapies intervene as early as possible in the biological progression of a disease, going right back to the start of the central dogma of biology. However, this always requires a delivery strategy due to the therapeutic nature. This need and limitless opportunity of genetic medicines has led TargoPep to focus on solving these delivery problems with its ADP platform. With the recent £10 million UK Government Science Innovation and Technology investment in oligonucleotides in Scotland, TargoPep is primed to be a key partner and enabler of the next generation of life changing therapeutics.^[5]

Dr Fergus McWhinnie, January 2024.

[1] a) Frankel, A. D., Pabo, C. O. Cell 1988, 55, 1189–1193. b) Green, M., Lowenstein, P. M. Cell 1988, 55, 1179–88.

[2] Sheppard, R. J. Pept. Sci. 2003, 9, 545.

[3] Richard, J.P., Melikov, K., Vives, E., Ramos, C., Verbeure, B., Gait, M.J., Chernomordik, L.V., Lebleu, B. J. Biol. Chem. 2003, 278, 585-590.

[4] Xie, J., Bi, Y., Zhang, H., Dong, S., Teng, L., Lee, R.J., Yang Z. Front. Pharmacol. 2020, 11, 697. [5] Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., Anderson, D. G. Nat. Rev. Genet.2014, 15, 541–555