Classification of peptidomimetics MCQs With Answer

Classification of peptidomimetics MCQs With Answer

Introduction: This quiz set explores the classification and design principles of peptidomimetics — chemically modified molecules that mimic peptide structure and function. It is intended for M.Pharm students preparing for advanced topics in Proteins and Protein Formulations. Questions cover common classification schemes (peptide-like, backbone-modified, non-peptide scaffolds), specific classes such as peptoids, β‑peptides and retro‑inverso peptides, design strategies (cyclization, stapling, amide isosteres), synthetic methods and the pharmacokinetic/biophysical rationale behind modifications. Use these MCQs to test and deepen your understanding of how structural changes influence stability, binding and therapeutic potential of peptidomimetics.

Q1. Which broad class in common peptidomimetic classifications describes non‑peptide small‑molecule scaffolds that mimic the spatial arrangement of peptide side chains?

• Class A — peptide backbone retained with side‑chain modifications
• Class B — backbone‑modified peptidomimetics (partial peptide character)
• Class C — non‑peptide small‑molecule scaffolds that mimic side‑chain topology
• Class D — glycopeptidomimetics with carbohydrate appendages

Correct Answer: Class C — non‑peptide small‑molecule scaffolds that mimic side‑chain topology

Q2. Which of the following is the correct definition of a peptoid?

• A peptide cyclized through a disulfide bridge
• An N‑substituted glycine oligomer where side chains are attached to the backbone nitrogen
• A peptide containing β‑amino acids
• A retro‑inverso peptide with reversed sequence and D‑amino acids

Correct Answer: An N‑substituted glycine oligomer where side chains are attached to the backbone nitrogen

Q3. Retro‑inverso peptidomimetics are characterized by which structural change?

• Substitution of α‑amino acids with β‑amino acids to form a 14‑helix
• Reversing the peptide sequence and replacing L‑amino acids with D‑amino acids to preserve side‑chain topology
• Replacing the amide bond with a triazole isostere
• Introducing hydrocarbon staples between side chains to lock an α‑helix

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

Q4. Which class of peptidomimetics is built primarily from β‑amino acids and often forms stable helical secondary structures resistant to proteolysis?

• Peptoids
• β‑peptides
• Retro‑inverso peptides
• Small‑molecule scaffolds (Class C)

Correct Answer: β‑peptides

Q5. What is the principal purpose of “stapling” an α‑helical peptide (hydrocarbon stapling)?

• To introduce glycosylation for receptor recognition
• To constrain helix conformation, increase helicity, protease resistance and cell permeability
• To convert the peptide into a peptoid by N‑substitution
• To break the helix and produce a random coil for better solubility

Correct Answer: To constrain helix conformation, increase helicity, protease resistance and cell permeability

Q6. Which of the following is a major advantage typically sought by designing peptidomimetics?

• Increased conformational flexibility to lower binding affinity
• Enhanced proteolytic stability and improved pharmacokinetic properties
• Maximizing the number of backbone amide NH donors to increase polarity
• Ensuring complete metabolic inertness by removing all heteroatoms

Correct Answer: Enhanced proteolytic stability and improved pharmacokinetic properties

Q7. Which backbone modification is commonly used as an amide bond isostere in peptidomimetic design?

• N‑alkylation to form peptoids that remove the amide NH donor
• Substitution of the α‑carbon with sulfur (thio‑α‑amino acids)
• Replacement of amide with an ester linkage to increase hydrogen bonding
• Insertion of a glycosidic bond between residues

Correct Answer: N‑alkylation to form peptoids that remove the amide NH donor

Q8. Which in silico method is most appropriate for initially identifying small‑molecule peptidomimetics that reproduce a peptide binding epitope?

• Pharmacophore modeling and virtual screening to match spatial arrangement of side‑chain features
• De novo protein folding simulations to predict full receptor structure
• Quantum mechanics calculations of entire peptide dynamics
• High‑throughput wet‑lab screening only, without computational input

Correct Answer: Pharmacophore modeling and virtual screening to match spatial arrangement of side‑chain features

Q9. In peptidomimetic classification by mimicry type, what does “topographical mimicry” refer to?

• Mimicking the peptide primary sequence exactly using D‑amino acids
• Mimicking the three‑dimensional spatial arrangement of key side chains required for function
• Replacing all peptide bonds with non‑rotatable linkers
• Adding glycosylation patterns to mimic glycopeptides

Correct Answer: Mimicking the three‑dimensional spatial arrangement of key side chains required for function

Q10. Which example best represents a Class A peptidomimetic (peptide‑like molecule that retains substantial backbone character)?

• Constrained cyclic peptide analogs using head‑to‑tail cyclization or lactam bridges
• Small heterocyclic scaffold that positions substituents like peptide side chains
• Non‑peptidic benzodiazepine scaffold used to mimic peptide turns
• Low‑molecular‑weight fragment discovered by fragment‑based drug design

Correct Answer: Constrained cyclic peptide analogs using head‑to‑tail cyclization or lactam bridges

Q11. Cyclization of a linear peptide typically improves which of the following properties most directly?

• Increase in the number of rotatable bonds to enhance flexibility
• Improved conformational restriction leading to increased target affinity and proteolytic stability
• Complete elimination of polar surface area
• Guaranteed oral bioavailability without further modification

Correct Answer: Improved conformational restriction leading to increased target affinity and proteolytic stability

Q12. Which concise definition best describes a peptidomimetic?

• A full‑length protein engineered to include non‑natural amino acids
• A small molecule or modified peptide that reproduces the biological activity of a peptide but with improved drug‑like properties
• A polysaccharide conjugate used to stabilize peptides in formulations
• An unmodified natural peptide used as a therapeutic without change

Correct Answer: A small molecule or modified peptide that reproduces the biological activity of a peptide but with improved drug‑like properties

Q13. Which solid‑phase synthetic method is routinely used for the efficient synthesis of sequence‑defined peptoids?

• Submonomer solid‑phase synthesis that alternates acylation and amine displacement steps
• Native chemical ligation of unprotected peptides in solution
• Enzymatic ligation using peptidyl transferase
• Synthetic glycosylation on resin to yield glycopeptoids

Correct Answer: Submonomer solid‑phase synthesis that alternates acylation and amine displacement steps

Q14. Which statement correctly describes the effect of retro‑inverso modification on peptide backbone hydrogen bond directionality?

• Hydrogen bond donors are preserved exactly as in the parent L‑peptide
• Backbone amide orientation is reversed, which can alter internal H‑bonding patterns while preserving external side‑chain display
• It converts all amide bonds into ester bonds increasing hydrogen bonding capacity
• It introduces additional backbone NH groups, increasing intramolecular bonding

Correct Answer: Backbone amide orientation is reversed, which can alter internal H‑bonding patterns while preserving external side‑chain display

Q15. Which limitation is commonly encountered when designing Class C non‑peptidic peptidomimetics for large protein–protein interaction (PPI) surfaces?

• They are too flexible to fit small enzyme active sites
• They may fail to reproduce extended, shallow binding surfaces required for many PPIs
• They always have excellent oral bioavailability which reduces potency
• They necessarily contain peptide bonds making them protease sensitive

Correct Answer: They may fail to reproduce extended, shallow binding surfaces required for many PPIs

Q16. Which helical secondary structure is most frequently observed in oligomers of β‑amino acids (β‑peptides)?

• α‑helix (3.6 residues per turn)
• 14‑helix (three residues per turn, stabilized by 14‑membered hydrogen bonds)
• β‑sheet with interstrand hydrogen bonding identical to α‑peptides
• Random coil exclusively due to flexible backbone

Correct Answer: 14‑helix (three residues per turn, stabilized by 14‑membered hydrogen bonds)

Q17. Which backbone modification specifically removes the backbone amide NH hydrogen bond donor and thus alters H‑bonding patterns?

• Introduction of β‑amino acids
• Conversion to peptoids (N‑alkylation of backbone nitrogen)
• Retro‑inversion of the peptide sequence
• Formation of an intramolecular disulfide bond

Correct Answer: Conversion to peptoids (N‑alkylation of backbone nitrogen)

Q18. Which therapeutic application is particularly well suited to peptidomimetics compared with unconstrained linear peptides?

• Acting as broad‑spectrum solvents in formulation
• Inhibition of intracellular protein–protein interactions where cell permeability and proteolytic stability are required
• Replacing small‑molecule enzyme substrates in metabolic pathways
• Serving as unmodified vaccine antigens without adjuvants

Correct Answer: Inhibition of intracellular protein–protein interactions where cell permeability and proteolytic stability are required

Q19. Which experimental approach is most commonly used to assess proteolytic stability of a peptidomimetic during early development?

• Measuring thermal denaturation temperature (Tm) by DSC only
• Incubation with relevant proteases or serum followed by HPLC/LC‑MS analysis of degradation products
• Evaluating color change upon addition to buffer as a proxy for stability
• Computational prediction solely, without experimental validation

Correct Answer: Incubation with relevant proteases or serum followed by HPLC/LC‑MS analysis of degradation products

Q20. When designing peptidomimetics to improve oral bioavailability, which physicochemical feature is most important to reduce?

• Lipophilicity (log P) to zero to maximize aqueous solubility
• Topological polar surface area and number of hydrogen bond donors to reduce membrane permeability barriers
• Molecular rigidity to allow complete unfolding in the GI tract
• Removal of all aromatic rings to prevent absorption

Correct Answer: Topological polar surface area and number of hydrogen bond donors to reduce membrane permeability barriers

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