Chapter 33 — Further Reading

A note before the list. This chapter is unusually well served by primary and regulatory sources, because engineered peptides are documented in enormous detail by the people who had to convince a regulator that the molecule was what they said it was. Where a claim in this chapter concerns a specific approved drug — a substitution, a fatty acid, a half-life — the source of record is the product's regulatory assessment, not a review article. Those documents are free.

Nothing below is a source of dosing or protocol information, and none of it should be read that way.

Tier 1 — Start here

Regulatory assessment reports for semaglutide, liraglutide, tirzepatide, and dulaglutide. European Medicines Agency public assessment reports and the corresponding US Food and Drug Administration review packages. These contain the exact molecular descriptions this chapter summarizes: which residue was substituted, where the fatty acid attaches, what spacer chemistry was used, what half-life was measured and in whom. Search the agency's website by product name and read the quality and clinical pharmacology sections. If you read only regulatory documents for the rest of this book, you will be better sourced than most people writing about peptides online.

A current review of half-life extension strategies for peptide therapeutics. Search terms: "half-life extension," "albumin binding," "acylation," "peptide therapeutics." Look for a review published within the last five years in a journal of medicinal chemistry or drug delivery. What you want from it is the comparison table — the same molecule class approached by lipidation, PEGylation, and fusion, with the trade-offs laid out side by side.

A textbook chapter or review on peptide drug discovery and modification. Any current medicinal chemistry text will have one. Read it for the systematic catalog of substitutions, which is far longer than this chapter's selection, and for the standard figures showing where modifications go.

The prescribing information for one lipidated peptide and one Fc-fusion peptide. Read the clinical pharmacology sections next to each other. The contrast in half-life, distribution, and immunogenicity reporting makes §33.6's "you are no longer making a peptide" concrete in a way no review article does.

Tier 2 — Go deeper

The primary literature on hydrocarbon stapling. Start with the original methodology papers on all-hydrocarbon crosslinking of alpha helices, then read at least one paper that is critical of cell-penetration claims. The field has a genuine, technical, long-running disagreement, and reading only one side of it will leave you more confident than the evidence supports. Search terms: "stapled peptide," "cytosolic access," "endosomal escape," "quantitative cell penetration."

The 2003 reevaluation of cell-penetrating peptide uptake and the fixation artifact. This paper is worth reading in full even though the finding is now standard, because it is a case study in how an assay artifact can shape a subfield. Search terms: "cell-penetrating peptides," "reevaluation," "fixation artifact," "cellular uptake mechanism."

The anti-PEG antibody literature. Both the pre-existing-antibody prevalence work and the clinical consequence work — accelerated blood clearance, and anti-drug antibody development in PEGylated uricase therapy for gout. Read enough to see that this was normal science conducted in the open.

Structural work on class B GPCRs. Cryo-electron microscopy structures of the GLP-1 receptor with peptide and with non-peptide agonists bound explain §33.7 far better than prose can: you can see the extended binding surface, and you can see how a small molecule manages a site built for a long peptide. Search terms: "GLP-1 receptor," "cryo-EM structure," "class B GPCR activation."

Late-stage clinical reports on oral small-molecule GLP-1 receptor agonists. For the ⚠️ rating in §33.7, go to the trial publications rather than press releases, and check the endpoints, the comparator, the discontinuation rates, and the duration.

Solid-phase peptide synthesis and the manufacturing consequences of non-proteinogenic residues. Pairs with Chapter 32. The industrial literature on manufacturing acylated peptides at scale is the place where §33.8's Lys34→Arg argument stops being an anecdote and becomes an engineering constraint you can see quantified.

Tier 3 — Specialist and historical

Merrifield's original solid-phase synthesis papers (from 1963 onward). The technique that made everything in this chapter possible, described by the person who invented it.

The early PEGylation literature of the 1970s and 1980s. Read it for the tone. The confidence that PEG was inert is visible, and it is instructive to watch a reasonable assumption being made by careful people.

Macrocycle drug discovery and the "beyond rule of five" literature. For readers who want to understand why cyclosporine's oral bioavailability was so hard to reproduce deliberately, and what the field now thinks governs membrane permeability in large, flexible molecules.

FcRn biology. The salvage pathway is a beautiful piece of cell biology in its own right, and the literature extends well beyond drug half-life into immunology and neonatal physiology.

Peptide display technologies — phage display, mRNA display — as the discovery engine behind modern macrocycle and constrained-peptide programs. This is where "how did anyone find that sequence" gets answered.

Patent literature for approved peptide analogs. Unglamorous and extremely informative. Composition -of-matter patents state exactly which positions were varied and what was claimed, which often reveals how much of the design space was explored before the marketed molecule was selected.

If you only do one thing

Download the regulatory assessment report for semaglutide and find the section that describes the molecule. Read the three modifications in the agency's own words, then read this chapter's §33.8 alongside it.

Two things will happen. First, you will see that everything in §33.8 is documented in a public file that anyone can read — including the Lys34→Arg substitution and its purpose, which is stated plainly in the manufacturing discussion and is invisible in essentially all popular coverage of the drug.

Second, and more usefully, you will acquire a habit. For any approved peptide you ever wonder about, there is a public document written by people who had to defend every claim in it to a skeptical regulator. That document is almost always better than the review article summarizing it, and it is always better than the marketing. Learning where it lives is worth more than any single fact this chapter contains.