Peptides have always carried the scent of promise. These short polymers of amino acids – fundamental to life – have intrigued chemists and biologists alike for well over a century. Filling a niche between small molecules and proteins, they offer the structural simplicity and synthetic accessibility of the former, and the biological specificity of the latter.
Since the start of the twentieth century, peptides have spent periods of time on the periphery of pharmaceutical development, and other stretches riding a wave of renewed interest. However, two things have persisted: Firstly, the hope has always been there; and secondly, the field of Peptide Science, and the myriad of supporting disciplines, continue to advance unrelentingly.
Now, a quarter of the way through the twenty-first century, we are better equipped than ever to exploit the tremendous clinical potential of peptides, and with recent blockbusters making it to the market, the belief is there. As such, peptides are gaining momentum and presently set firmly in the crosshairs of the drug development sector.
A Brief History
If we step back to where this all began, the story of peptide science is littered with the names of giants; Emil Fisher first described the synthesis of a peptide, glycyl-glycine, in 1901.
In the years that followed, Fisher’s student Max Bergmann introduced the first reversible amino protecting group, Cbz, allowing for the stepwise assembly – amino acid by amino acid – of peptides in solution. Around this time, therapeutic interest in peptides was also developing, with scientists at the University of Toronto able to extract and purify insulin from ox pancreas; they went on to show its efficacy in the treatment of diabetes in humans and exemplifying the clinical potential of peptides to treat disease, leading to the Nobel Prize in 1923 being awarded to Frederick Banting and John MacLeod.
These two emerging fields – peptide synthesis and peptide therapeutics – would converge later in a landmark piece of work by Vincent du Vigneaud who, in 1953, described the structure and synthesis of the peptide hormone Oxytocin, a 9 amino acid cyclic peptide used clinically to induce childbirth, earning him the Nobel Prize in 1955. This also led to the creation of an award in his honour, and, on a personal note, I was delighted to recently learn that my Post Doctoral supervisor, Prof. Dek Woolfson, is set to receive the 2025 Vincent du Vigneaud Award from the American Peptide Society. He joins a long list of outstanding scientists recognised for their contribution and honours the lasting impact that du Vigneaud had on the field.
Shortly after du Vigneaud, the next seismic shift to arrive was the advent of Solid-Phase Peptide Synthesis (SPPS) by Bruce Merrifield, first reported in 1963. In this new technique and using the Boc protecting group described by Louis Carpino just a few years earlier, Merrifield described the assembly of a peptide in a stepwise fashion whilst attached to a solid support, rather than solution-phase synthesis typically used in organic chemistry. This enabled the use of a large excess of reagents to drive reactions towards 100% completion, and allowed for easy washing of the growing peptide, and the removal of excess reagents following each coupling and deprotection step.
This contribution from Merrifield would, in time, revolutionise the field, ushering in the so-called “Golden Age of Peptide Synthesis”, and see him awarded the Nobel Prize in 1984.
Advances in Synthesis Through the Years
In the decades that followed the introduction of SPPS, techniques for the synthesis of peptides were unceasingly refined.
To this day, researchers across industry and academia continue to push the envelope to make the chemical synthesis of even the most difficult peptides, faster, better, cleaner, green-er, and more efficient than before. Collectively, this body of work has yielded tremendous advances, the likes of which Fisher could not possibly have imagined when he first synthesised the simplest of dipeptides.
There have been many step-changes in the field, all of which are far too numerous to describe here, but some key amongst them include:
- The advent of Fmoc-based SPPS by Eric Atherton and Bob Sheppard, reported in 1981, which makes use of the Fmoc protecting group (which, reminiscent of Boc for Merrifield’s SPPS breakthrough, was also described a few years beforehand by Louis Carpino), and requires far milder reaction conditions than had previously been the mainstay
- Native chemical ligation (NCL) first described by Steve Kent in 1994, which allows for the traceless conjugation of two unprotected peptide fragments, opening the door to much larger assemblies, as well as techniques for expressed protein ligation which have been used to elegantly answer questions of basic biology by Tom Muir and others
- Multiple orthogonal conjugation strategies, or “click chemistries” (e.g. CuAAC as described by both Meldal and Sharpless laboratories in 2002, which lead to a shared Nobel Prize in 2022) that have allowed for the facile conjugation of peptides to innumerable different kinds of other molecules
Alongside these and other large-step changes in how we go about making peptides, there have been other incremental advances: for example, an improved protecting group here, and a more efficient coupling reagent there.
Taken together, all these developments over the last 124 years have compounded to the point where the synthesis of a simple peptide that once took years to complete, and was truly ground-breaking at the time, can now be performed by an undergraduate student over a matter of days. The landscape has completely changed and will continue to do so at pace. What was once difficult has been made routine, what was once impossible is now achievable, and questions that were once unthinkable, are now being asked.
Supporting Disciplines
This kind of progress seen over the years is not limited to peptide chemistry, and it could be argued that peptide science, more generally, has seen even greater advances. It is also worth remembering that it does not sit in isolation from other disciplines.
Quite to the contrary, the field of Peptide Science brings together a truly diverse group of scientists with skillsets and backgrounds that span the length and breadth of science – from the mathematically and computationally-minded researchers who drive the rational design of peptides, through to the chemists and separation scientists able to make these in silico designed compounds a reality, right through to the biophysicists, biologists, physiologists, pharmacologists, toxicologists, medics, as well as other scientists at the bench who drive the design-make-test-learn cycle.
All these fields have seen astronomical growth over recent years that has enabled researchers to ask more questions, many of which arrive at the answer of “a peptide”.
Digital and Structural Revolution
Amongst all these developments in peptide science, and in its related and underpinning disciplines, perhaps the ones that have had the greatest impact are the interrelated avalanches in computational power, structural data, and AI.
In just my time in the field, I have seen a 20-fold increase in structures deposited into the PDB, and X-ray crystallisation and cryo-EM techniques evolving from something highly specialised to one that is now streamlined and routine in many laboratories. This huge collection of protein structural data, coupled with advances in genetic sequencing, Cryo-EM, computing, and AI, means the so-called “Protein-Folding Problem” is now generally considered to have been solved, with the 2024 Nobel Prize in Chemistry awarded to David Baker, as well as scientists behind Google’s DeepMind.
Perhaps pessimistically, the “Protein-Folding Problem” is something that I thought would never be solved during my lifetime. This gigantic boost to structure-based drug design has revolutionised how we approach peptide discovery programs. The ability to model folding patterns, simulate docking interactions, and predict degradation pathways in silico has shifted the design process from empirical iteration to one that is truly rational and works. It has been a revolution that has opened the doors to many. These tools are now no longer the preserve of large pharma companies either; even small biotechs and start-ups now wield predictive models to accelerate the development of peptide libraries that are smarter, more stable, and more likely to succeed than ever before.
Outstanding Hurdles & Solutions
Of course, the “Peptide Therapeutics Problem”, if I may coin such a term, is far from being solved. Like where we were with the “Protein Folding Problem” just 10 years ago, we know a lot, we have learned plenty from our mistakes along the way, and we now have several cases we can point at as exemplars of success. However, we currently lack generalised, broad-brushed solutions to the challenges that have stymied the therapeutic application of peptides for decades. What we have at our disposal now though – through the fruits of 124 years of peptide science – is a toolkit of solutions to tackle these limitations.
One of the Achilles’ heels of many peptides – their fragility in plasma – has been addressed through techniques that include backbone cyclisation strategies, sidechain-to-sidechain stapling, an almost infinite number of options with regards to incorporating non-natural amino acids, N-methylation of backbone amides, and so on. Done well, this renders peptides resistant to proteolytic degradation, whilst still maintaining efficacy for their receptor.
In fact, many of the most exciting developments in the field have concerned macrocyclic peptides, which can bind protein surfaces previously considered “undruggable”. Indeed, the same structural rigidity conferred by many of these strategies can bring both improved stability and enhanced receptor affinity – a true win-win.
A further criticism long levelled at peptide-based therapeutics relates to their generally poor pharmacokinetic profile across the board. Indeed, any API is only as good as its ability to reach its site of action intact, and at an effective local concentration.
Historically, peptides have been hindered by delivery limitations, especially for oral and CNS applications. But here too, progress is being made. Cell-penetrating peptides, lipid nanoparticles, and permeation enhancers have enabled systemic delivery routes to be used that were once deemed implausible.
The recent approval of orally-administered Semaglutide finally provides the symbolic break from the dogma that peptides must be injected. New generations of delivery devices, from microneedle patches to slow-release implants, will also continue to reshape what is thought possible.
Green Challenges
Aside from challenges in the therapeutic use of peptides that must be tackled, another problematic area for the field, which is ripe for improvement, and becoming increasingly important, concerns peptide synthesis specifically. It may seem odd, but in many ways, we are perhaps now further from solving what could be called the “Peptide Synthesis Problem” than we were 20 or 30 years ago.
That is not to say that we have somehow regressed in our ability to prepare complex peptides – indeed, quite the opposite is true – but because, rightly, the goal posts on what we might consider success have shifted.
Traditional methods for synthesising peptide are about as green as burning peat to keep a tent warm. That may sound glib, but we must do better. With an average PMI of ~13,000, SPPS’s “green” credentials are entirely unacceptable in today’s world. Researchers are trialling a variety of approaches to improve this, including the use of greener solvents, liquid-phase assembly and so on.
It is ironic that while SPPS in solvents such as DMF heralded the arrival of the “Golden Age of Peptide Synthesis”, finally walking away from such technologies and solvents in the future will likely be the harbinger of the next “Green Age of Peptide Synthesis.
It is also worth remembering too, green assembly of peptides is just half of it; we also need to purify them. Nowadays however, if the research team (or industrial partner) so wishes, peptides can be prepared using techniques that are green-er than those used in the past. However, the field remains desperately in need of a green shake-up, of the kind of magnitude seen when Merrifield first introduced us to SPPS – a true green revolution.
Looking to the Future
So, why has interest in peptides surged so dramatically in recent years, to the point where they might even be considered “fashionable” again? Part of the answer lies in the biology itself, which excites us for the same reason it excited the founders of the field.
Peptides are our endogenous messengers – they regulate appetite, sleep, inflammation, cognition, and immunity. By mimicking or modulating these signals, peptides offer a degree of precision few other modalities can match, and if there is not an endogenous peptide ligand for your receptor of interest from which to build, one can set out to design a de novo one. As medicine shifts toward personalisation and pathway targeting, the high specificity and low systemic toxicity of peptides have become prized attributes.
Another reason for the excitement is the acceptance that the peptide need not be the therapeutic solution on its own but may serve as a component of the solution.
Particularly exciting is the emergence of hybrid modalities: peptide–drug conjugates, peptide–oligonucleotide constructs, and even peptibodies that bridge the gap between peptides and full biologics. These combinations exploit the specificity and programmability of peptides to deliver cargo – be it a toxin, an siRNA, or a small molecule – directly to diseased tissues.
In oncology, for example, tumour-penetrating peptides linked to chemotherapeutic payloads are showing encouraging selectivity and efficacy. In rare genetic diseases, peptide-oligonucleotide conjugates are being explored to enable cell-type specific delivery of splice-switching antisense therapies.
There is also a commercial reality at play. The successes of GLP-1 receptor agonists in type 2 diabetes and obesity, and Merck’s MK-0616 to treat hypercholesterolemia, have validated peptides as high-value therapeutics. These drugs are not only effective and actively delivering positive impact on patient’s lives, but they are also blockbuster assets generating billions annually. That level of success attracts capital and catalyses entire industries with success driving (and funding) further success. It also attracts people: none of what has been achieved to date would have been possible without great minds deciding to tackle the problems in front of us, and this will continue to be the case.
Startups with peptide platforms are thriving, academic funding bodies are supporting research around peptides, and large pharma companies are investing heavily in internal peptide capabilities.
But amidst all this excitement, we must remind ourselves of the challenges that remain. Oral bioavailability – while there have been some success stories – remains a nut that has yet to be fully cracked. Blood-brain barrier penetration remains elusive without clever chemistry or invasive routes of administration. Immunogenicity, though rare, can still complicate development, particularly for modified or xenogeneic peptides.
Despite progress, the large-scale manufacture and purification of some peptides remains a technical and financial bottleneck, and, as touched upon earlier, it must be considerably greener. These challenges are not insurmountable, but they do require concerted and collaborative effort, and an investment in basic research.
Final Thoughts
As we reflect on the current landscape and how peptides sit within the broad spectrum of therapeutic development and medicine, it is hard not to be struck by a sense of momentum and belief. The road ahead will require continued innovation, rigour, and regulatory foresight, but we are better equipped than ever to tackle the challenges presented by taking a peptide from discovery through to the clinic, and we have many recent examples to show us it can be done. The field is bursting with creativity and purpose; I truly believe there has never been a better time to be working with peptides.
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