Chapter 33 Exercises

How to use these. Work them with the chapter open. Items marked † are harder — they ask you to reason across chapters, hold two ideas in tension, or evaluate a claim rather than recall a fact. No answers are given here; several items have more than one defensible response, and the value is in being able to say why yours is defensible.

A standing rule for every item. Nothing here is a protocol, and nothing here should be read as guidance about taking anything. These exercises are about evaluating claims, not about acting on them.

Set A — The toolkit and the four goals (§33.1–§33.2)

A1. State Chapter 4's two exits by which a peptide leaves the body, and say in one sentence each why closing only one of them is insufficient.

A2. Name the four engineering goals from §33.1. For each, name one modification from the chapter that serves it.

A3. Draw or describe the structural difference between alanine and Aib. Explain in your own words why that difference stops a protease without stopping the receptor at position 8 of semaglutide.

A4. Aib is non-proteinogenic. Explain what that means and what it forces about how an Aib-containing drug must be manufactured.

A5. Exendin-4 resists DPP-4 without human engineering. What residue is responsible, and what does this example suggest about the relationship between "engineered" and "optimal"?

A6. † §33.1 claims that the features an enzyme recognizes and the features a receptor recognizes "frequently overlap." Explain why that would be expected on general grounds — that is, why should a protease and a receptor be interested in some of the same parts of a molecule?

A7. D-amino acids resist mammalian proteases. Give the reason, and then give the reason a D-substitution is nonetheless risky for activity.

A8. Name three properties that unnatural residues are used to tune, with one example of what each change accomplishes.

A9. † Semaglutide's tolerance of Aib at position 8 is described in the chapter as partly luck. Construct the counterfactual: describe what the GLP-1 analog field would look like if position 8 had been a critical receptor contact. What alternative strategies from later sections would have had to carry the load?

Set B — Constraint, size, and duration (§33.3–§33.6)

B1. Name the three routes to cyclization described in §33.3 and give one drug or molecule that uses each.

B2. Explain the entropic argument for why cyclization can improve affinity without changing a single contact with the receptor.

B3. Octreotide is shorter than somatostatin, contains D-residues, and is cyclized. State what each of those three features contributes.

B4. † §33.3 notes that octreotide's truncation narrowed its receptor-subtype profile — a Goal 3 outcome from a Goal 1 intervention. Explain why goals in this chapter's map are not cleanly separable in practice, using this example.

B5. Describe the three benefits claimed for hydrocarbon stapling and rank them by how well supported the chapter says they are.

B6. † A paper reports that a fluorescently labeled stapled peptide "shows strong intracellular localization" in fixed cells. List three specific reasons this observation may not support the claim being made, and name one experiment that would be more convincing.

B7. Explain the albumin-binding mechanism of lipidation in a way that accounts for all three of its benefits: filtration resistance, protease shielding, and reservoir behavior.

B8. Liraglutide, semaglutide, and insulin detemir all use fatty-acid acylation and have very different durations. Identify the design levers responsible.

B9. Why does a spacer sit between the peptide and the fatty acid in semaglutide? What would you expect to go wrong without one?

B10. Give three reasons PEGylation fell out of favor for peptides, in the chapter's order of increasing importance.

B11. † PEGylation is described as having been displaced by "normal scientific progress" rather than scandal. Defend that framing against someone who insists a technique is only abandoned when something is wrong with it. Then state what evidence would make the scandal framing correct.

B12. Explain the FcRn salvage pathway in three sentences, and say why it makes Fc fusion more powerful than simply increasing molecular weight.

B13. † §33.6 says the trade-off of fusion is that "you are no longer making a peptide." Enumerate at least four concrete consequences of crossing that line, drawing on Chapter 32.

Set C — The anchor and multi-agonist design (§33.7–§33.9)

C1. Define peptidomimetic and state the four liabilities the approach is trying to discard.

C2. Explain why small molecules succeeded early at opioid and angiotensin receptors but only recently at the GLP-1 receptor. Use the class A / class B distinction.

C3. † §33.7 calls peptidomimetics "the endpoint of the engineering arc." Argue for that reading, then argue against it — is a small molecule at a peptide receptor really the end of peptide engineering, or a different field entirely?

C4. List semaglutide's three modifications, with position and purpose for each.

C5. Which of semaglutide's three modifications closes which of Chapter 4's exits? Which closes neither?

C6. Explain, in terms a careful non-chemist could follow, why removing lysine 34 makes the acylation reaction produce one product instead of a mixture.

C7. † The Lys34→Arg substitution has no patient benefit. Write two paragraphs: one arguing it is therefore a compromise imposed by manufacturing, and one arguing it is excellent drug design. Then say which you find more persuasive and why.

C8. Semaglutide's half-life is roughly 5,000 times that of native GLP-1. State what happened to its receptor activity, and give the general lesson §33.8 draws from that.

C9. Native GLP-1's short half-life is described as a feature rather than a flaw. Explain the physiological reasoning.

C10. Contrast the two multi-agonist architectures on five dimensions: ratio adjustability, pharmacokinetics, stability testing, immunogenicity, and what it takes to change the ratio.

C11. † Suppose a trial showed a fixed-ratio dual agonist outperforming a coformulated pair on a weight endpoint. State precisely what that result does and does not establish about the two architectures.

Set D — What engineering cannot fix, and using the frame (§33.10, Dossier)

D1. Name Chapter 2's four termination mechanisms and sort them into engineerable and non-engineerable.

D2. Explain the sentence: "a longer-lasting agonist pushes harder on exactly the machinery that shuts the signal down."

D3. Give four things §33.10 says engineering cannot fix, with one example each from elsewhere in the book.

D4. † State the general rule of §33.10 in one sentence, then stress-test it: find one modification in this chapter that appears to violate the rule, and explain why it does or does not.

D5. Fill in Field 4 for semaglutide from memory, then check it against the chapter.

D6. Pick one compound from your own dossier whose Field 4 entry is "unmodified native sequence." Write the two follow-up questions §33.10 and the Dossier section say that entry forces, and try to answer them from public sources. Record what you could not find.

D7. † A product page describes a compound as "bioengineered for superior stability and enhanced receptor affinity." Using the chapter's four goals, write the three questions you would ask to determine whether this sentence describes anything at all — and predict the answers.

D8. Explain to a friend, in five sentences and without jargon, why semaglutide is not "stronger" than the hormone it is based on.

D9. † Chapter 1 §1.6 ruled intracellular targets largely off-limits for peptides. Two sections of this chapter push against that conclusion in different ways. Identify them, and say how confident you are in each, and on what basis.

D10. Write a one-paragraph summary of this chapter for someone who will read nothing else in the book. It must include both what engineering achieves and what it cannot reach.