[Image courtesy of Sai Life Sciences]
The answer is related to the convergence of innovation across several key areas in discovery and development.
- Enhanced stability and delivery: The latest leaps forward in the development of orally bioavailable peptide-based drugs have been significant. Development of novel chemistries around macrocyclization, side chain modifications and use of un-natural amino acids has helped to address the historical challenges around rapid breakdown in the body, and these, alongside targeted delivery, improved formulations and enhanced bioavailability, have helped establish peptides as therapeutic agents.
- Expanding therapeutic applications: Beyond the traditional areas of diabetes and hormone therapy, researchers are exploring the application of peptides in cancer therapy, immune diseases, infectious diseases and even neurological disorders. The ability of peptides to target specific pathways and interact with previously undruggable targets unlocks new therapeutic avenues and applications.
- Use of AI and Machine learning: Development of modern computational methods have resulted in the rapid acceleration of de novo design of peptides, particularly in the relation to large proteins, identifying potential binding sites and designing new molecules to interact with them.
- Improved manufacturing: Another innovation has been the synthesis of peptides in a more efficient and cost-effective manner. Large scale liquid phase peptide synthesis (LPPS), as well as solid phase peptide synthesis (SPPS) with continuous chromatography and chemoenzymatic peptide synthesis, offer high efficiency and scalability of peptide preparation. This means that the large quantities required for drugs and drug candidates are now accessible.
[Image courtesy of Sai Life Sciences]
Peptides lead, where others follow
Peptides can be engineered to interact with a large area of a target protein, ensuring specificity and high target-binding affinities, a well-defined mechanism of action, minimal drug–drug interaction potential, and the ability to exploit key protein–protein interactions in the cellular environment. These advantages are driving interest in biological targets that have eluded the scientific community for several years. Alongside this, greater understanding of biological systems and developments within the fields of X-ray and cryo-EM, including areas of protein/peptide modelling, have enabled accessibility to data at the molecular level, leading to the design and optimization of peptide-based therapeutics with greater accuracy.
The high target-specificity of peptides has been exploited by conjugation with high potency payloads, for example peptide–drug conjugates (PDCs) or radioligands. These new therapies have shown tremendous potential, and it’s likely that these factors are also contributing to the resurgence of interest in the development of peptides for pharmaceutical use.
| Small molecules | Peptides | Biologics (e.g. MABs) | |||
| Advantages | Disadvantages | Advantages | Disadvantages | Advantages | Disadvantages |
| Low cost | Lack of target specificity | High binding affinity | Poor oral bioavailability | Target specific | No oral bioavailability |
| Facile preparation | Undruggable targets | Target specific | Challenging to prepare | Longer half-life | Heat sensitive |
| Good oral bioavailability | Rapid breakdown and excretion | Low toxicity | Short half-life | Low risk of drug–drug interaction | Membrane impermeable |
Expertise in therapeutic peptides
There are, however, two main challenges that still need further advancement to fully exploit the potential of peptides. The first is in relation to their diversity of synthesis, and the second is their optimization and characterization in vivo.
In terms of synthesis, peptide preparation is non-trivial. Amino acid composition, overall length, solubility and end-user application all need to be considered. While automated peptide synthesisers are now available, specialist chemical knowledge is still required in setting up the reactions and characterisation of the final products. In addition, purification, solubilization, analysis and storage can be challenging and often depend upon the final peptide sequence, with different peptides requiring different approaches.
Alongside this are the inherent challenges to developing peptides for therapeutic purposes. However, the synthetic optimization of peptide physicochemical properties can be tuned for specific applications, for example to facilitate oral absorption or enhance cellular permeability; aspects that were previously difficult to achieve. Advances in formulation science5 have played a role in this, such as the development of additives that can enhance absorption of peptides through the intestinal membrane.
While there are challenges to overcome in both the large-scale synthesis and use of peptides within pharmaceuticals, the clear advantage that small molecules, or even biologics, had in terms of known behaviors is diminishing and the knowledge and understanding of peptide-behaviours in vivo is rapidly advancing, allowing fine-tuning of properties and tailored engineering of solutions.
About the author: Santosh Kulkarni leads the medicinal chemistry team in discovery services at Sai Life Sciences. Holding a PhD from ICT (formerly UDCT) and with post-doctoral research experience at the National Institutes of Health (NIH), Santosh has over two decades of expertise in drug discovery working on various modalities of small molecules, PROTACs, ADCs, and peptides.
References
- Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, Wang X, Wang R, Fu C. Therapeutic peptides: current applications and future directions. Signal Transduction and Targeted Therapy, 7:48, 2022. https://doi.org/10.1038/s41392-022-00904-4
- Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg. Med. Chem., 26 (10), 2700-2707, 2018. https://doi.org/10.1016/j.bmc.2017.06.052
- Rossino G, Marchese E, Galli G, Verde F, Finizio M, Serra M, Linciano P, Collina S. Peptides as Therapeutic Agents: Challenges and Opportunities in the Green Transition Era. Molecules, 28 (20), 7165-7203, 2023. https://doi.org/10.3390/molecules28207165
- Quianzon CC, Cheikh I. History of Insulin. JCHIMP, 2, 18701-18703, 2012. https://doi.org/10.3402/jchimp.v2i2.18701
- Renukuntla J, Vadlapudi AD, Patel A, Boddu SHS, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int. J. Pharm., 447, 1, 75-93, 2013. https://doi.org/10.1016/j.ijpharm.2013.02.030
Filed Under: Biospecimens, Drug Discovery
