Chapter 33 Quiz

Twenty-two items. Work through them before opening the answer key.

1. Chapter 4 established two routes by which a peptide leaves the body. They are:

A. Hepatic metabolism and biliary excretion B. Proteolysis and renal filtration C. Receptor internalization and lysosomal degradation D. Exhalation and sweat

2. Aib (2-aminoisobutyric acid) differs from alanine by:

A. A second methyl group on the alpha carbon B. Having the D rather than the L configuration C. A sulfur atom in the side chain D. An additional carbon in the backbone

3. The most immediate practical consequence of using a non-proteinogenic residue such as Aib is that:

A. The peptide becomes orally bioavailable B. The molecule cannot be produced by ribosomal expression and must be made chemically C. Receptor affinity increases D. The peptide can cross the blood-brain barrier

4. In semaglutide, the substitution at position 8 primarily serves to:

A. Increase receptor affinity B. Abolish the DPP-4 cleavage site C. Provide a site for fatty-acid attachment D. Reduce immunogenicity

5. The Lys34→Arg substitution in semaglutide exists primarily to:

A. Extend half-life B. Improve receptor selectivity C. Ensure the acylation reaction produces one defined product rather than a mixture of attachment isomers D. Reduce gastrointestinal side effects

6. Semaglutide's fatty diacid at position 26 defeats which elimination route?

A. Proteolysis by DPP-4 B. Renal filtration C. Hepatic first-pass metabolism D. Receptor-mediated internalization

7. Approximately how does semaglutide's half-life compare with that of native GLP-1?

A. About twice as long B. About ten times as long C. Roughly one to two minutes versus roughly one week D. Roughly one hour versus roughly one day

8. Semaglutide's receptor activity, relative to native GLP-1, is best described as:

A. Substantially greater B. Essentially unchanged C. Substantially reduced but compensated by duration D. Directed at a different receptor entirely

9. Which best states the thermodynamic reason cyclization can improve affinity?

A. It increases the molecule's molecular weight B. It adds new hydrogen bonds with the receptor C. It reduces the entropic cost of adopting the bound conformation D. It increases the peptide's positive charge

10. Octreotide is:

A. A linear 30-residue GLP-1 analog B. A cyclic eight-residue somatostatin analog containing D-amino acids C. An Fc-fusion protein D. A PEGylated enzyme

11. Which claim about stapled peptides is the most contested?

A. That stapling increases helicity B. That stapling improves protease resistance C. That stapling delivers peptides to the cytosol at useful concentrations D. That stapling can improve binding affinity

12. A 2003 reevaluation of cell-penetrating peptide uptake showed that:

A. Peptides never enter cells B. Standard cell fixation redistributes peptide and can produce false images of cytosolic delivery C. Endosomes do not exist in cultured cells D. Fluorescent labels always abolish peptide activity

13. Lipidation extends half-life principally by:

A. Covalently locking the peptide to a cell membrane B. Promoting reversible, non-covalent binding to albumin C. Blocking the peptide's N-terminus D. Increasing the peptide's net positive charge

14. Liraglutide (~13 hours), semaglutide (~1 week), and insulin detemir (flat basal profile) illustrate that:

A. Lipidation always produces weekly dosing B. The same tool is tuned by chain length, diacid terminus, and spacer to hit different duration targets C. Fatty acids only work on GLP-1 analogs D. Longer fatty acids always reduce potency

15. Which is not among the reasons PEGylation fell out of favor for peptides?

A. Steric hindrance of receptor binding B. Documented anti-PEG antibodies C. Poor metabolism and tissue accumulation with chronic dosing D. PEG's inability to increase hydrodynamic radius

16. "Accelerated blood clearance" refers to:

A. Faster elimination of a repeat dose because antibodies have marked it for removal B. Kidney failure caused by PEG C. The rapid clearance of native peptides D. Increased cardiac output during infusion

17. FcRn extends the half-life of Fc-containing proteins by:

A. Preventing their synthesis B. Binding them in acidified endosomes and returning them to circulation instead of the lysosome C. Cross-linking them into aggregates D. Blocking renal filtration by charge repulsion

18. The principal trade-off of Fc or albumin fusion is that:

A. Half-life becomes too short B. Receptor affinity is always abolished C. The product is no longer a peptide and carries a biologic's manufacturing requirements and costs D. The construct cannot be given by injection

19. Orforglipron is significant because it is:

A. A PEGylated GLP-1 peptide B. A non-peptide small molecule activating a class B GPCR that a peptide normally binds C. The first stapled peptide approved for oncology D. An Fc-fusion amylin analog

20. Compared with a coformulated pair such as CagriSema, a single-molecule dual agonist such as tirzepatide:

A. Has a ratio of receptor activities fixed by its structure and not adjustable after the fact B. Has two independent pharmacokinetic profiles C. Is always more effective D. Requires two separate immunogenicity programs

21. Which pair of Chapter 2's termination mechanisms is beyond the reach of molecular engineering?

A. Degradation and clearance B. Desensitization and downregulation C. Degradation and desensitization D. Clearance and downregulation

22. The chapter's general rule is best stated as:

A. Engineering can solve any peptide problem given enough iterations B. Engineering solves delivery problems and only delivery problems C. Engineering always increases potency D. Engineering is chiefly a manufacturing discipline

Answer key **1. B.** Proteolysis and renal filtration. Both must be closed for a long half-life; closing one alone buys little. **2. A.** Aib is alanine with a second methyl on the alpha carbon. That extra methyl sits where a protease needs empty space. **3. B.** No codon, no tRNA, no ribosome will incorporate it — so the molecule must be assembled chemically (or by a hybrid route), which determines the manufacturing strategy, cost structure, and release testing (Chapter 32 §32.6). **4. B.** Position 8 (GLP-1(7-37) numbering) is where DPP-4 cuts. Aib abolishes the site. Notably, receptor binding is not degraded — an outcome the chapter calls partly fortunate, since enzyme and receptor recognition features usually overlap. **5. C.** With two lysines, acylation would go to position 26 on some molecules, 34 on others, and both on some, producing attachment isomers. Arginine keeps the charge but is not a nucleophile under the acylation conditions, so the reaction becomes regioselective by construction. This modification has no patient benefit; it is a manufacturing and quality-control decision. **6. B.** The albumin complex is far too large for the glomerulus. Note that albumin binding also shields the peptide from proteases, but its defining role here is defeating filtration. **7. C.** Roughly one to two minutes to roughly one week. **8. B.** Essentially unchanged. This is the chapter's central point: the receptor pharmacology was never the problem, because evolution had optimized it. What was engineered was survival. **9. C.** A linear peptide samples many conformations and pays an entropic cost to adopt the one that binds. Constraining it pre-pays that cost. **10. B.** Eight residues, disulfide-cyclized, with D-phenylalanine and D-tryptophan and a modified C-terminus; engineered from somatostatin, whose native half-life is a couple of minutes. **11. C.** Cytosolic delivery. Helicity, affinity, and protease resistance are well supported; intracellular access is genuinely contested, with documented assay artifacts and disagreement about endosomal escape. **12. B.** Fixation redistributes membrane-associated and endosome-trapped peptide, producing images that were read as cytosolic delivery but were artifacts of sample preparation. **13. B.** Reversible, non-covalent albumin binding. The complex is too large to filter, the bound peptide is shielded from proteases, and albumin acts as a slowly releasing reservoir. **14. B.** The point of §33.4: the modification is tuned, not merely applied. **15. D.** PEG does increase hydrodynamic radius — that is the mechanism, and it works. The other three are the real reasons. **16. A.** A documented immunological phenomenon, not a theoretical one. **17. B.** The salvage pathway: FcRn binds Fc at endosomal pH and releases it at blood pH. It is why antibodies last weeks, and the same receptor also recycles albumin. **18. C.** You have left the peptide category. Cell-culture expression, biosimilar rather than generic competition, and orders-of-magnitude higher cost of goods follow. **19. B.** A small molecule at the GLP-1 receptor. Rated ⚠️ as of 2026 — late-stage and unapproved; the approach is real and not yet proven at scale. **20. A.** Fixed ratio is the defining property of the single-molecule architecture, and changing it requires designing a new molecule. Neither architecture is obviously better. **21. B.** Desensitization and downregulation are decisions the target cell makes, not properties of the ligand. Worse, a longer-lasting agonist pushes harder on exactly that machinery. **22. B.** And its corollary: everything in Part III that fails, fails somewhere else.