Peptidomimetics: Design strategies and therapeutic applications MCQs With Answer

Peptidomimetics: Design strategies and therapeutic applications MCQs With Answer

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Introduction

Peptidomimetics are engineered molecules that mimic the biological activity of peptides while overcoming their limitations such as poor oral bioavailability, rapid proteolysis, and short plasma half-life. This quiz collection focuses on design strategies—backbone and side-chain modifications, cyclization, stapling, isosteric replacements, and conjugation approaches—and their therapeutic applications across oncology, infectious disease, metabolic and cardiovascular targets. Questions emphasize rational design principles, synthetic and analytical techniques, ADME optimization, and representative drug examples. The set is tailored for M.Pharm students preparing for advanced medicinal chemistry examinations, combining conceptual depth with applied scenarios to strengthen understanding and exam readiness.

Q1. What best defines a peptidomimetic?

  • A small molecule that blocks peptide receptors by covalent modification
  • A compound that imitates the structure and/or function of a peptide but with improved drug-like properties
  • A natural peptide produced by microorganisms to mimic host hormones
  • A peptide labeled with isotopes for imaging studies

Correct Answer: A compound that imitates the structure and/or function of a peptide but with improved drug-like properties

Q2. Which modification is characteristic of peptoids (N‑substituted glycine oligomers)?

  • Side chains attached to the alpha-carbon and increased backbone hydrogen bonding
  • Side chains attached to the backbone nitrogen (N‑substitution) and resistance to proteases
  • Alpha‑methylation of residues to stabilize beta‑sheets
  • Replacement of the peptide bond by a tetrazole linkage

Correct Answer: Side chains attached to the backbone nitrogen (N‑substitution) and resistance to proteases

Q3. Retro‑inverso peptide design involves which of the following?

  • Reversing the amino acid sequence and replacing L‑residues with D‑residues to preserve side‑chain topology
  • Replacing all amide bonds with esters to increase flexibility
  • Crosslinking side chains to lock a beta‑turn conformation
  • Grafting peptide side chains onto a small molecule scaffold without changing chirality

Correct Answer: Reversing the amino acid sequence and replacing L‑residues with D‑residues to preserve side‑chain topology

Q4. Which structural feature is most responsible for the increased proteolytic stability of beta‑peptides?

  • Presence of N‑terminal acetylation exclusively
  • Backbone extension by an extra methylene per residue creating a beta‑amino acid backbone
  • Attachment of polyethylene glycol chains
  • Incorporation of disulfide bonds between cysteines

Correct Answer: Backbone extension by an extra methylene per residue creating a beta‑amino acid backbone

Q5. Hydrocarbon stapling of alpha‑helical peptides is typically achieved by which reaction?

  • Olefin metathesis between non‑natural alpha‑methylated amino acids at i and i+4 positions
  • Oxime ligation between N‑terminal aldehyde and hydroxylamine side chain
  • Click chemistry between cysteine residues
  • Amide bond formation between side chains

Correct Answer: Olefin metathesis between non‑natural alpha‑methylated amino acids at i and i+4 positions

Q6. Which modification most directly reduces backbone hydrogen bond donors and can improve cell permeability of peptides?

  • N‑terminal acetylation
  • N‑methylation of amide nitrogens
  • Cyclization through disulfide bridges
  • C‑terminal amidation

Correct Answer: N‑methylation of amide nitrogens

Q7. Which functional group is commonly used as a carboxylic acid bioisostere in peptidomimetic design (e.g., angiotensin receptor blockers)?

  • Tetrazole
  • Thiol
  • Nitrate
  • Phosphate

Correct Answer: Tetrazole

Q8. Bortezomib is an example of which type of peptidomimetic therapeutic?

  • Proteasome inhibitor containing a boronic acid warhead as a peptide mimic
  • Peptidic hormone analog used for diabetes management
  • Small‑molecule GPCR agonist unrelated to peptides
  • A cyclic peptide antibiotic that targets membranes

Correct Answer: Proteasome inhibitor containing a boronic acid warhead as a peptide mimic

Q9. Which marketed drug is a classic example of a peptidomimetic ACE inhibitor?

  • Metoprolol
  • Captopril
  • Atorvastatin
  • Losartan

Correct Answer: Captopril

Q10. Which synthetic technique is most commonly used for rapid assembly of defined peptide and peptidomimetic sequences in research labs?

  • Solid‑phase peptide synthesis (SPPS)
  • Kolbe electrolysis
  • Grignard polymerization
  • Fischer esterification

Correct Answer: Solid‑phase peptide synthesis (SPPS)

Q11. Native chemical ligation is primarily used to:

  • Join two unprotected peptide fragments through a chemoselective reaction to form a native peptide bond
  • Introduce lipid moieties to peptides to improve cell uptake
  • Attach fluorescent labels selectively to side chains
  • Cleavage of signal peptides during secretion

Correct Answer: Join two unprotected peptide fragments through a chemoselective reaction to form a native peptide bond

Q12. Which strategy is commonly used to extend the systemic half‑life of peptidomimetics by reducing renal clearance?

  • Pegylation (PEGylation)
  • Incorporation of D‑amino acids exclusively at the C‑terminus
  • Introduction of multiple free carboxylates to increase hydrophilicity
  • Reducing molecular size to less than 500 Da

Correct Answer: Pegylation (PEGylation)

Q13. Which analytical technique is most useful for rapidly assessing peptide secondary structure (alpha‑helix vs beta‑sheet) in solution?

  • Circular dichroism (CD) spectroscopy
  • Mass spectrometry (MS)
  • Infrared fluorescence microscopy
  • Gas chromatography

Correct Answer: Circular dichroism (CD) spectroscopy

Q14. For designing peptidomimetics that disrupt protein–protein interactions mediated by an alpha‑helix, which approach is typically most effective?

  • Designing constrained alpha‑helix mimetics such as stapled peptides to present key side chains in an ordered geometry
  • Replacing all residues with glycine to increase flexibility
  • Incorporating large polar linkers to increase solubility at the expense of structure
  • Using linear unmodified peptides without conformational constraints

Correct Answer: Designing constrained alpha‑helix mimetics such as stapled peptides to present key side chains in an ordered geometry

Q15. Which change is most likely to increase oral bioavailability of a linear peptide?

  • Increasing the number of free amide NH groups
  • N‑methylation of backbone amide nitrogens and cyclization to reduce flexibility
  • Adding multiple charged carboxylate groups
  • Extending the peptide length by adding polar residues

Correct Answer: N‑methylation of backbone amide nitrogens and cyclization to reduce flexibility

Q16. Replacement of an amide bond by a thioamide in a peptidomimetic typically results in:

  • Increased susceptibility to proteolysis and loss of activity
  • Altered H‑bonding geometry, modestly increased protease resistance, and spectroscopic shifts
  • Loss of chirality at the adjacent alpha‑carbon
  • Spontaneous cleavage in aqueous buffers

Correct Answer: Altered H‑bonding geometry, modestly increased protease resistance, and spectroscopic shifts

Q17. Which statement about peptidomimetic HIV protease inhibitors (e.g., saquinavir) is correct?

  • They are unmodified natural peptides that are rapidly degraded orally
  • They are designed as non‑cleavable peptidomimetics that mimic the protease substrate transition state
  • They function by binding to viral DNA polymerase
  • They are beta‑peptides that form stable 14‑helices to inactivate the protease

Correct Answer: They are designed as non‑cleavable peptidomimetics that mimic the protease substrate transition state

Q18. Which effect is a common drawback of heavy PEGylation of peptidomimetics?

  • Complete elimination of immunogenicity without affecting potency
  • Potential reduction in receptor binding affinity due to steric hindrance
  • Increased renal clearance due to decreased molecular size
  • Conversion of the compound into an irreversible enzyme inhibitor

Correct Answer: Potential reduction in receptor binding affinity due to steric hindrance

Q19. Which computational method is most appropriate for sampling conformational flexibility of a peptidomimetic helix in explicit solvent?

  • Molecular dynamics (MD) simulations
  • Quantitative structure–activity relationship (QSAR) using only 2D descriptors
  • Simple docking without protein flexibility
  • Elementary thermogravimetric analysis (TGA)

Correct Answer: Molecular dynamics (MD) simulations

Q20. Which modification is typically employed to reduce immunogenicity while retaining activity of therapeutic peptide mimetics?

  • Incorporation of non‑natural amino acids and backbone modifications (e.g., D‑residues, N‑methylation)
  • Increasing the length of the peptide to more than 100 residues
  • Replacing all hydrophobic residues with tryptophan
  • Administering peptides exclusively via inhalation

Correct Answer: Incorporation of non‑natural amino acids and backbone modifications (e.g., D‑residues, N‑methylation)

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