The Renaissance and Industrial (r)Evolution of Peptide and Oligonucleotide Therapeutics

What do you get when the Renaissance, Industrial Revolution, and Evolution converge? Exactly what peptide and oligonucleotide therapeutics are experiencing today.

We have come a long way from hormone replacement therapy for peptides or niche, rare diseases for oligos. Who would have thought that in 2026 we would have not one but two oral peptide therapeutics? Or that we would be treating heart disease (high cholesterol) or even Alzheimer’s disease with oligonucleotides?

Rewind 75 to 125 years when these therapeutic modalities were born out of basic science. The foundation for what we have today was founded on Emil Fischer’s initial synthesis of dipeptides in 1901 and Gobind Khorana’s work in the 1970s to synthesize the first oligonucleotides.

In the beginning, synthetic peptides were short and consisted of the 20 natural amino acids. Oxytocin and vasopressin were the first synthetic peptides approved in the 1950s. An explosion occurred post-1963 when Bruce Merrifield developed solid phase peptide synthesis. Over the years, the length and complexity of peptide therapeutics have increased exponentially. It is now common for peptide therapeutics to be cyclic or conformational constrained and include unnatural amino acids or lipid modifications.  This diversity of chemistry enhances the pharmaceutical properties of peptides, allowing them to have better stability both chemically and biologically.

Oligonucleotides have followed a similar path to peptides. The solution synthesis of the phosphodiesterase bond quickly leveraged the solid-phase synthesis framework developed for peptides. We also saw a revolution in nucleic acid chemistry with the advent of phosphamidate chemistry by Caruthers in the 1980s, and more recently, to improved stability of both DNA and RNA, inclusion of a host of backbone modification chemistries like 2’-MOE, 2’-F and LNA as well as modifications to the sugar. Additionally, modifications like GalNAC conjugation allowed for highly selective delivery to the liver. Since the first approved oligo therapeutic fomivirsen (Vitravene™) in 1998, we have seen an explosion of approvals with the current count upward of two dozen.

The resurgence of interest in peptide therapeutics owes its success to the family of GLP-1 agonists. Discovered in 1992 and approved in 2005, exenatide (Byetta™) was the first out the gate, but suffered from its short half-life. Extended-release formulations like Bydureon™ helped but traction for peptides began with the advent of second generation GLP-1 agonists like liraglutide and semaglutide and the observation that this class of molecules could result in weight loss and a possible treatment for obesity. The next generation peptides like tirzepatide, a dual agonist (GLP-1 and GIP) and the upcoming triple agonist (GLP-1, glucagon & GIP), retatrutide are adding to the demand for peptide therapeutics. Combined with oral administration, this success comes with challenges like large-scale manufacturing. Advances in chemical synthesis, purification and supply chains have allowed multi-metric ton scale synthesis of peptides.

Oligonucleotide therapeutics have also seen rapid growth driven by antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) with key successes and validation of this therapeutic modality in spinal muscular atrophy (Spinraza®), Duchenne muscular dystrophy (Duvyzat®) and hypercholesterolemia (Leqvio®). The beauty of oligonucleotide therapeutics is their ability to alter disease at the transcript level, bypassing the complexity of protein translation, post-translational modification and translocation. Targets for oligo therapeutics can come from our understanding of disease genetics or disease risk genes (GWAS data). Key therapeutic areas for growth include cardiometabolic disease and neurology.

What does the future hold for these therapeutic modalities? For both peptides and oligos, innovation is coming in three main buckets. 1) Chemistry and manufacturing, 2) Delivery, and 3) New targets and mechanisms of action.

Chemistry and Manufacturing. We are seeing parallel trajectories for both peptides and oligos. The larger indications being tackled by these modalities will require innovations in scale-up manufacturing with greater emphasis on sustainability, developing new chemistries and approaches that will have less impact on the environment. This will come from finding solvents that are more environmentally friendly in both synthesis and purification. Reducing the cost of goods will be an important consideration as these therapeutics gain commercial success.

Delivery. Key to having an effective therapeutic is getting it to the right site of action. Selectivity and specificity both impact safety and efficacy. Additionally, sites of action previously unobtainable for these modalities will expand the universe of potential therapeutic indications. The large, polar properties of these modalities has made delivery challenging. Just as GalNAC revolutionized the treatment of liver disease by its ability to selectively target hepatocytes, the transferrin receptor is being exploited to target muscle and the blood-brain-barrier (brain shuttles). Additional technologies and approaches will be needed to perhaps target specific cell types for our therapeutic interventions.

Targets and Mechanisms of Action. Peptides have been essentially relegated to extracellular targets; however, cyclic peptides and the use of cell-penetrating peptides have opened the possibility of intracellular targeting. With the plethora of opportunities inside the cell, we are beginning to see the design of peptide therapeutics to intracellular targets including transcription factors!

Oligonucleotide targets are also ever expanding with ASO, siRNA, aptamers and mRNA paving the way for potential gene editing mechanisms-of-actions. The use of artificial intelligence (AI) in the design of oligo therapeutics could help accelerate lead selection by enhancing specificity and reducing off-target interactions.

These are exciting times for both peptide and oligonucleotide therapeutics.