Peptide Drug Discovery Raison d’Etre: Engineering Mindset, Design Rules and Screening Tools
Fifty years took the field from natural hormones to intracellular targets to vast macrocyclic libraries. A practitioner's survey sets out what changed, what it cost, and the design rules and screening tools that turned accumulated intuition into method.
Three waves, still running: receptor and extracellular targets, then intracellular ones, then the macrocyclic libraries that now drive the field.
Peptide drug discovery has a habit of being declared impossible and then quietly succeeding. Too big for a pocket, too fragile for a gut, too short-lived for a dose — and yet somatostatin analogues, GLP-1 agonists and macrocyclic protein–protein interaction inhibitors keep arriving in clinics. What changes is not the chemistry’s fundamental difficulty but the accumulated knowledge of how to work around it.
That accumulation is the subject of an opening chapter by Tomi K. Sawyer of Maestro Therapeutics and Kaustav Biswas of Merck & Co., written for an American Chemical Society Symposium Series volume. It is a practitioner’s survey rather than a research report: an attempt to set down what the field has learned, illustrated by cases the authors have watched or worked on, and framed around an argument about mindset.
Three waves
The organising idea is that peptide drug discovery has come in three waves over roughly fifty years, and that none of them has ended.
The first wave went after receptors and extracellular targets. The major academic and pharmaceutical effort of the 1960s and 1970s pursued GPCR ligands — somatostatin, α-melanocyte-stimulating hormone, enkephalin, gonadotropin-releasing hormone, cholecystokinin — and extracellular enzymes including angiotensin-converting enzyme and renin. The logic was straightforward: the target is outside the cell, so the peptide does not have to get in.
The second wave turned inward, to intracellular targets and the protein–protein interfaces that small molecules struggle to address. This is the harder problem, because now the molecule must cross a membrane, and the chapter treats permeability as the discipline’s defining obstacle.
The third wave is about libraries: vast and diverse macrocyclic collections built synthetically, as in one-bead-one-compound approaches, or biologically, through phage, mRNA and DNA display. The authors describe this as the current driving force, amplified by computational and in silico methods including artificial intelligence, and by structural biology — X-ray crystallography, cryo-EM, NMR and mass spectrometry — resolving how these molecules actually sit on their targets.
Cases, chosen to teach something
The chapter moves through examples rather than arguing abstractly, and the selection is instructive in itself.
On the extracellular side: somatostatin, a disulfide-bridged 14-mer, and the marketed analogues it produced — octreotide, pasireotide, lanreotide. The melanocortin peptides and their receptor-selective descendants. GLP-1 and the analogues that solved its two liabilities, DPP-4 cleavage and a half-life of minutes, through substitution at position 2 and fatty-acid conjugation that parks the drug on albumin.
Then more recent and more structurally adventurous work: a bispecific bicyclic peptide designed to bring immune cells to tumours; zilucoplan, a complement C5 inhibitor that had reached Phase III testing, and which the authors note is a genuinely complex macrocycle; a tricyclic PCSK9 inhibitor with good protease and blood stability.
On the intracellular side the chapter begins where the field does, with cyclosporin A — the natural product that proved a large peptide can be orally available and cell-permeable, and which remains the benchmark against which permeability is measured. Then a homodimeric XIAP-BIR3 inhibitor, a bicyclic cell-penetrating NEMO antagonist that combines a fixed cell-penetrating motif in one ring with a randomised binding ring in the other, a CFTR-associated ligand antagonist, dual MDM2/X stapled α-helical peptides, and KRAS-targeted peptides.
Rules, and the tools to test them
The final section is the one the title points at. The authors set out the chemical levers available for tuning a peptide’s physicochemical and biophysical properties: N-methylation, cyclic amino acids, Cα-methylation, β-amino acids, peptoids built on N-substituted glycine, and conformational constraint through ring size and bicyclisation.
Their practical recommendation is benchmarking. Permeability should be assessed against well-characterised references such as cyclosporin A, with attention to which mechanism is actually operating — passive permeability, cationic partitioning and endocytosis, or lipophilic partitioning and translocation are not the same thing and do not respond to the same design changes.
They point to the now-substantial array of computational, biophysical and biological screening tools that make both predictive design rules and experimental permeability analysis possible, and close by noting that formulation — permeability enhancers enabling oral bioavailability — will contribute significantly to the next generation of peptide therapeutics.
The modus operandi of peptide drug hunters nowadays is significantly impacted by an engineering mindset, design rules and screening tools.
What kind of document this is
It is worth being clear about the genre. This is a review chapter, not primary research: it reports no new experiments, and its authority rests on selection and synthesis rather than on data generated for the occasion. Its case studies are drawn from published work by many groups, and it is explicit that each of the three waves continues rather than having been superseded.
Read that way, its value is in the framing. The chapter argues that peptide drug discovery has passed from craft to method — that there now exist stated rules, benchmarks and screening cascades where there was once accumulated intuition — and it offers the three-wave structure as a way of understanding why the field’s problems changed shape as it advanced.
The authors’ own phrase for the point of all of it is the one they put in the title: the raison d’être of peptide drug discovery is delivering therapies for unmet medical need. The engineering mindset is the means, not the end.
Source
Tomi K. Sawyer and Kaustav Biswas. “Peptide Drug Discovery Raison d’Etre: Engineering Mindset, Design Rules and Screening Tools.” Chapter 1 in an American Chemical Society Symposium Series volume (ACS Symposium Series 1417). © 2022 American Chemical Society.
Affiliations: Maestro Therapeutics, Southborough, Massachusetts; Merck & Co., Inc., Boston, Massachusetts. Corresponding author: Tomi K. Sawyer.
The underlying work is the authors’ own review and synthesis of the published literature, and the case studies discussed are the work of the many groups cited within it. Maestro Chronicle provides the editorial presentation.