EF - Glycomimetic Drugs

Question 1

Q1: What is a glycomimetic and why is it useful? (3)

Answer 1

• A glycomimetic is a molecule that mimics the structure and function of a natural glycan.
• Example: Carbafucose (8β) – a fucose analog used to produce afucosylated therapeutic antibodies.
• 8β is metabolized to GDP-carbafucose, but not incorporated into glycoproteins, making it ideal for broad use in various cell types.

Question 2

Q2: What are the key roles of carbohydrates on cell surfaces? (6)

Answer 2

• Cover the cell surface and secreted proteins.
• Extend outward to interact with other biomolecules (“molecular handshakes”).
• Recognized by lectins, antibodies, and CAZys (carbohydrate-active enzymes).
• Essential for protein folding and protein–protein interactions.
• Serve as first points of contact for pathogens (bacteria, viruses, toxins).
• Can be modulated or mimicked in disease for therapeutic purposes.

Question 3

Q3: What is the hit-to-lead process in glycomimetic drug discovery? (3)

Answer 3

• Hit compound: initial molecule that binds a biological target, often with micromolar (µM) affinity.
• Optimized to increase binding strength (goal: nanomolar [nM] range).
• Must compete with natural glycans and overcome low intrinsic affinity of carbohydrate–lectin interactions.

Question 3

Q4: How do carbohydrates bind to proteins? (5)

Answer 3

• Hydrogen bonding – sugars form H-bonds with amino acids.
• Hydrophobic interactions – bottom of sugar ring interacts with hydrophobic residues.
• C–H π interactions – sugar C–H bonds interact with aromatic protein residues.
• Desolvation – release of bound water increases entropy, driving binding.
• Drug design should use rigid, aromatic scaffolds to enhance binding and compete with water.

Question 4

Q5: How do lectins and carbohydrate-processing enzymes differ as drug targets? (5)

Answer 4

Lectins:

• Low binding affinity (mM range) and high off-rates.
• Promiscuous binding and no catalytic activity.
• Often multi-domain proteins with complex structures.

Enzymes:

• High affinity for reactants, low for products.
• Perform chemical transformations.
• More specific binding and tunable kinetics, making them better drug targets.

Question 5

Q6: What is antiadhesive therapy and how do glycomimetics help? (4)

Answer 5

• Bacterial lectins (adhesins) allow pathogens to stick to host epithelial cells or form biofilms.
• Blocking lectin–glycan interactions prevents pathogen colonization and infection.
• Antiadhesive therapy aims to disrupt adhesion, not kill bacteria.
• Glycomimetics offer non-antibiotic, resistance-resistant strategies to treat infections.

Question 6

Q7: What are limitations of using native carbohydrates as drugs? (4)

Answer 6

• Highly hydrophilic and polar → cannot cross intestinal epithelial cells.
• Contain multiple hydroxyl, carboxyl, and sulfate groups → poor permeability.
• Flexible structure with many rotatable bonds → high energy cost for binding.
• High desolvation cost makes protein binding inefficient in vivo.

Question 7

Q8: What are key structural features of Influenza A virus? (4)

Answer 7

• Enveloped virus with flexible (non-spherical) morphology.
• Two key surface proteins:
  • HA (hemagglutinin) – a lectin that binds sialic acid on host cells.
  • NA (neuraminidase) – an enzyme that cleaves sialic acid for viral release.
• Genetic material is negative-sense RNA.
• Viruses vary in HA receptor preference (2,3 vs. 2,6 sialic acid linkages).

Question 8

Q9: What are the key steps in the Influenza A virus life cycle? (6)

Answer 8

1. Attachment – HA binds sialic acid on host cell surface.
2. Entry – Virus enters via endocytosis.
3. Replication – Viral RNA-dependent RNA polymerase converts viral RNA to mRNA.
4. Translation – Viral proteins synthesized in cytoplasm.
5. Assembly – Viral RNA and proteins assemble into new virions.
6. Release – NA cleaves sialic acid, freeing virions to infect other cells.

Question 9

Q10: How do glycomimetics block influenza virus function? (3)

Answer 9

• Glycomimetic inhibitors mimic sialic acid and bind to neuraminidase (NA).
• Prevents NA from cleaving sialic acid → new virions remain attached to host cells.
• This blocks viral release and limits infection spread.

Question 10

Q11: What are two clinically used glycomimetic antivirals? (2)

Answer 10

• Tamiflu (oseltamivir) – oral NA inhibitor; most successful glycomimetic drug.
• Relenza (zanamivir) – inhaled NA inhibitor; too polar for oral delivery.

Question 11

Q12: What is the overall significance of glycomimetics in drug design? (4)

Answer 11

• Glycans regulate many key biological processes in health and disease.
• Lectins and CAZys are viable but challenging drug targets.
• Glycomimetics must overcome low binding affinity and poor drug-like properties of native sugars.
• Glycomimetic drugs (e.g. Tamiflu) offer validated, market-approved therapies for infectious diseases.