Chapter 35 — Quiz

Twenty-two items. Multiple choice unless marked otherwise. Answers and explanations are in the collapsed key at the bottom — work all twenty-two before opening it, because several items are designed so that the wrong answers are the ones people actually believe.

1. Which of the following best describes the four routes to a peptide drug?

  • a) Four competing methods, of which the newest has superseded the others
  • b) Find it in nature; modify an endogenous ligand; select from a library; design it computationally
  • c) Extraction, fermentation, synthesis, and recombinant expression
  • d) Discovery, preclinical, clinical, and post-marketing

2. The chapter describes venoms as "pre-optimized pharmacological libraries." The strongest justification for that phrase is:

  • a) Venoms contain more distinct molecules than any synthetic library
  • b) Venom peptides are already approved as drugs
  • c) Evolution has selected venom components for fast, potent, specific action on vertebrate nervous, cardiovascular, and muscular targets — which is the design brief of a drug
  • d) Venoms are natural, and natural molecules are better tolerated

3. Why are venom peptides so often highly selective?

  • a) Venom glands can only produce one type of molecule at a time
  • b) Selectivity is metabolically cheap and effective; an indiscriminate venom would have to be delivered in bulk to disable anything in particular
  • c) Prey animals evolve resistance to non-selective toxins
  • d) Selectivity is an artifact of how toxinologists purify venom components

4. Exendin-4 was identified in the venom of:

  • a) The Brazilian pit viper (Bothrops jararaca)
  • b) The cone snail Conus magus
  • c) The Gila monster (Heloderma suspectum)
  • d) The African clawed frog (Xenopus laevis)

5. Exendin-4 resists cleavage by human DPP-4 because:

  • a) It is not a peptide
  • b) It carries a fatty acid chain that blocks enzyme access
  • c) It circulates bound to albumin
  • d) The residue at the position corresponding to GLP-1's cleavage site differs from the human sequence

6. Exenatide was approved in:

  • a) 1985
  • b) 1998
  • c) 2005
  • d) 2014

7. Short answer. In one sentence each, state (i) what the lizard solved and (ii) what chemistry still had to solve afterward.

8. Which statement about the exenatide story is the chapter's actual conclusion?

  • a) Nature is a better designer than chemists, and discovery should be prioritized over engineering
  • b) The lizard was a lucky accident with no general lesson
  • c) Nature supplied the lead and chemistry supplied the drug; discovery and optimization are different activities with different tools
  • d) Exenatide remains the best drug in its class

9. Captopril is:

  • a) A peptide isolated from pit viper venom
  • b) A modified version of teprotide with a longer half-life
  • c) A small molecule, not a peptide, designed to reproduce the key interactions of venom-derived peptides
  • d) A peptidomimetic that must still be injected

10. Teprotide's fatal practical problem as a medicine was that it:

  • a) Was too toxic at therapeutic doses
  • b) Had to be injected, which is unsuitable for a chronic asymptomatic condition
  • c) Did not actually lower blood pressure in humans
  • d) Could not be manufactured at scale

11. Ziconotide derives from ω-conotoxin MVIIA and must be given intrathecally because:

  • a) It is destroyed by liver metabolism
  • b) Its target is in the spinal cord and it does not cross the blood-brain barrier
  • c) Intrathecal delivery reduces its cost
  • d) It causes injection-site reactions when given subcutaneously

12. Magainins were identified in the skin of the African clawed frog by:

  • a) John Eng
  • b) George Smith
  • c) Michael Zasloff
  • d) David Baker

13. The principal disadvantage of starting from an endogenous ligand (route 2) is:

  • a) The physiology is usually unknown
  • b) You inherit the parent hormone's selectivity profile, including its off-target activity
  • c) Endogenous ligands cannot be chemically modified
  • d) Regulators will not approve molecules based on human hormones

14. The invention at the heart of phage display is:

  • a) A method for synthesizing billions of peptides at once
  • b) A physical link between a displayed peptide and the DNA encoding it
  • c) A way of predicting which peptides will bind a target
  • d) A cell-free translation system

15. Phage display, and directed evolution of enzymes, were recognized with a share of the Nobel Prize in Chemistry in:

  • a) 2005
  • b) 2012
  • c) 2018
  • d) 2024

16. Ribosome display and mRNA display permit larger libraries than phage display chiefly because:

  • a) They use non-natural amino acids
  • b) They are faster
  • c) They are cell-free, so library size is not capped by transformation efficiency
  • d) They select for higher-affinity binders

17. Short answer. Complete and defend the sentence: "Display technologies do not design anything; they are ______, industrialized."

18. Class B GPCRs matter to this book because:

  • a) They are the only receptors peptides can bind
  • b) They include the GLP-1, GIP, glucagon, PTH, and calcitonin receptors — the targets of a large share of the peptide drugs discussed here — and they were historically very hard to crystallize
  • c) They are found only in the central nervous system
  • d) They cannot be studied by cryo-EM

19. AlphaFold2's decisive result came at:

  • a) CASP14, in 2020
  • b) The Nobel ceremony, in 2024
  • c) A DeepMind press conference, in 2018
  • d) The Human Genome Project's completion, in 2003

20. Which of the following is not one of the four limitations the chapter attributes to structure prediction?

  • a) Structure is not function
  • b) Many short peptides have no single stable structure to predict
  • c) The predictions are less accurate for large globular proteins than for short peptides
  • d) Predicting a structure is not predicting a drug

21. The claim form "AI has revolutionized drug discovery" is rated ⚠️ because:

  • a) The structure-prediction result was never independently verified
  • b) The claim conflates finding candidate molecules with producing approved drugs, and clinical attrition is governed by efficacy and toxicity in humans rather than by candidate supply
  • c) Computational methods have produced no useful results
  • d) The Nobel Prize committee overstated the achievement

22. Short answer. State the chapter's general rule about pipelines and constraints, then apply it to one example that is not drug discovery.

Answer key **1 — b.** The four routes are: find it in nature, start from an endogenous ligand and modify it, screen an enormous library and select what binds, design it computationally. Option (a) is the error the chapter spends §35.1 and §35.10 dismantling: the routes are roughly chronological but all four remain in active use, and the newest has not retired the oldest. Option (c) lists manufacturing methods (Chapter 32); option (d) lists development phases. **2 — c.** The phrase is justified by the *selection criteria*, not by library size or by naturalness. Fast onset, potency at minute quantities, and action on vertebrate nervous, cardiovascular, and muscular systems are simultaneously what a venom needs and what a drug specification asks for. Option (b) inverts the argument — the approvals are the consequence, not the reason. Option (d) is the naturalness fallacy of Chapter 1. **3 — b.** The argument is economic. Venom is expensive to produce and slow to regenerate, so a molecule that binds one target with picomolar affinity is a far better investment than one that binds forty targets weakly. Selection therefore pushes venom components toward precisely the property pharmacologists try to engineer. **4 — c.** The Gila monster, *Heloderma suspectum*. Work associated with John Eng, in the early 1990s. (a) is the captopril lineage; (b) is ziconotide; (d) is the magainins. **5 — d.** The residue at the position corresponding to GLP-1's DPP-4 cleavage site differs from the human sequence, so the enzyme arrives and does not cut. (b) and (c) describe semaglutide's albumin-binding fatty acid — an engineered solution to a *different* problem, renal clearance. **6 — c.** 2005, as the first GLP-1 receptor agonist to reach the market. **7 —** (i) The lizard solved DPP-4 cleavage: exendin-4 carries a residue at the critical position that the human enzyme does not recognize as a substrate, which is the exact modification Chapter 33's chemists later arrived at by design. (ii) Chemistry still had to solve duration — exendin-4 does nothing about renal clearance, and the drugs that displaced exenatide added an albumin-binding fatty acid to extend the half-life from hours to days. Nature supplied the lead; chemistry supplied the drug. **8 — c.** Option (a) is the comfortable misreading the chapter explicitly refuses; option (b) discards the lesson entirely. The whole point is that both halves of the sentence are load-bearing. **9 — c.** Captopril is a small molecule and the earliest commercially important peptidomimetic in medicine. It was designed by Ondetti, Cushman, and colleagues to reproduce the key interactions of the venom-derived peptides without being a peptide, and was approved in the early 1980s. **10 — b.** Teprotide worked — it lowered blood pressure and validated ACE inhibition as a strategy. It was a peptide, so it had to be injected, and an injected antihypertensive is not a practical treatment for a chronic, asymptomatic condition managed by millions of people. **11 — b.** The target — N-type voltage-gated calcium channels on presynaptic terminals — is in the spinal cord, and the molecule does not cross the blood-brain barrier. The delivery problem was solved surgically rather than chemically. **12 — c.** Michael Zasloff, in the late 1980s. John Eng is exendin-4; George Smith is phage display; David Baker is de novo protein design. **13 — b.** The advantage of route 2 is that the target, the receptor, and the physiology are all known from the start. The cost is that the endogenous ligand's whole activity profile comes along, which is why GLP-1 agonists cause nausea, somatostatin analogs affect gallbladder motility and glucose, and GnRH agonists produce an initial flare. **14 — b.** The physical link between the displayed peptide and its encoding DNA is what allows the winners of a selection to be *identified*. Without it, a billion peptides in a tube are anonymous. **15 — c.** 2018, to George Smith and Greg Winter for phage display, shared with Frances Arnold for directed evolution of enzymes. (2024 is AlphaFold and de novo design — Hassabis, Jumper, and Baker.) **16 — c.** Library size in phage display is capped by how many distinct variants can be transformed into bacteria. Cell-free systems remove that cap. (a) is a genuine additional benefit but not the reason for the size advantage. **17 —** "Selection." The full statement: display technologies do not design anything — there is no model of the target and no reasoning about which side chain points where. They generate enormous variation, apply a physical filter, keep survivors, and repeat. That is evolution stripped to variation and differential survival, run on a bench in about a week. It is a compliment, not a criticism: selection works without requiring you to understand the target. What it yields is a sequence that binds, with no explanation attached. **18 — b.** The family is the target of a large share of the peptide drugs in Parts II and V, and its historical resistance to crystallization meant the engineering of Chapter 33 was done substantially blind until cryo-EM changed that. (d) is exactly backwards. **19 — a.** CASP14, in 2020 — a blind assessment in which predictions are scored against experimental structures that have not been published. The Nobel Prize followed in 2024. **20 — c.** This is reversed. Structure prediction performs best on stably folded globular proteins and least well on short flexible peptides, which have no single conformation to predict — and short flexible peptides are exactly the class of molecule this book is about. The genuine four are: structure is not function; short peptides frequently have no single structure; predicting a structure is not predicting a drug; and the predictions are predictions, with confidence lowest where disorder is highest. **21 — b.** Note what the rating does *not* say. The structure-prediction advance itself is rated ✅ as a research tool — decisively demonstrated and extremely broadly adopted. The ⚠️ attaches to the *claim form*, because it swaps the stage that got faster for the stage that decides outcomes. What would change it: a cohort of computationally designed peptides completing Phase 3 with approval rates materially above historical base rates. **22 —** The rule: *a technology that improves one stage of a pipeline improves the whole pipeline only if that stage was the constraint.* Acceptable examples include a faster kitchen in a restaurant whose constraint is the number of tables; a faster compiler in an organization whose constraint is deciding what to build; a wider on-ramp feeding a highway that is already jammed. A strong answer also names the case where the improvement *is* the constraint, since the rule is not a general argument against technology — it is an argument for identifying the bottleneck before claiming credit for the whole system.