Drug Targets & Transport Proteins

• Exam #1 is scheduled for Tuesday, February 8, 2022, during class.
• A study guide outline is available in the module.
• Students requiring SAS accommodations should email them.
• Grades will be posted after the weekend.

Miscellaneous Drug Targets

• Drugs target transport proteins, structural proteins, biosynthetic building blocks, protein synthesis, protein-protein interactions, cell membrane lipids, carbohydrates, antigens, and antibodies.

Transport Protein Drug Targets

• Transport proteins' active sites bind and transport specific molecules across a membrane
• Drugs can block the active site of transport proteins.
• Agents binding to transport proteins prevent neurotransmitter re-uptake (e.g., dopamine, serotonin, noradrenaline).
• Blocking re-uptake results in increased levels of affected neurotransmitters and mimics the effect of neurotransmitter agonists.

Cocaine

• Cocaine is a reuptake inhibitor for dopamine in the central nervous system, causing euphoric effects.
• Cocaine is a reuptake inhibitor of noradrenaline in the peripheral nervous system.
• This drug suppresses hunger.

Antidepressants

• Fluoxetine (Prozac), citalopram, and escitalopram are antidepressants.
• These drugs are selective serotonin reuptake inhibitors.
• A lack of serotonin in the brain is linked to depression, so blocking serotonin uptake prolongs its action.

Sibutramine

• Sibutramine is a reuptake inhibitor of serotonin, noradrenaline, and dopamine.
• Sibutramine has been used as an anti-obesity agent because increased serotonin reduces appetite.
• Chemically related to amphetamines, sibutramine was withdrawn from the market in 2010 due to side effects.

Methylphenidate (Ritalin)

• Methylphenidate (Ritalin) is a reuptake inhibitor for noradrenaline and dopamine.
• It is used to treat attention deficit hyperactivity disorder (ADHD).

Agents Acting on Structural Proteins: Viral Structural Proteins

• Viruses consist of nucleic acid encapsulated in a protein coat called a capsid.
• The capsid must be dissembled for infection of the host cell.
• Drugs can prevent the uncoating process by binding
• Viral proteins interact with host cell proteins to allow viral entry into the cell.

Enfuvirtide

• gp41 helices fold to form more helices drawing the virus and host cell together, leading to fusion.
• Enfuvirtide is a 36 amino acid polypeptide.
• Enfuvirtide has been used against HIV since 2003.
• Enfuvirtide acts as a fusion inhibitor by binding to gp41 to prevent the folding of helices, which blocks fusion.

Tubulin

• Cell division involves the polymerization and depolymerization of microtubules using tubulin as a building block.
• Drugs can disrupt the process by either binding to tubulin to stop polymerization or by binding to microtubules to stabilize and prevent depolymerization.
• These actions interrupt the balance needed for cell division.
• Useful as anticancer and anti-inflammatory treatments

Agents Acting on Structural Proteins

• Colchicine inhibits polymerization and is used in gout to reduce neutrophil movement into joints.
• It is only prescribed for acute attacks due to side effects.
• Vinva alkaloids (vincristine, vinblastine, vindesine, and vinorelbine) bind and prevent polymerization and are being studied as anticancer agents.

Biosynthetic Building Blocks: Cell Wall

• Vancomycin is an antibacterial agent.
• It caps the building blocks used in bacterial cell wall synthesis.
• Vancomycin contains a peptide chain that forms H-bonds with the terminal D-alanyl-D-alanine moieties of NAM/NAG peptides.

Protein Chain Terminators

• Puromycin is an antibiotic that mimics the terminus of an aminoacyl-tRNA molecule, bringing an amino acid to the ribosome to add to growing chain.
• It enters the ribosome and has the amino group required for growing peptide addition.
• The peptide chain is transferred to puromycin and releases from the ribosome, resulting in a stunted chain.

Agents Acting on Lipids

• Amphotericin B treats athlete's foot through antifungal action.
• It interacts with lipids and sterols in cell membranes to build tunnels.
• Cell contents drain and the cell is killed off through this process.
• One half of its structure includes hydrophobic double bonds, while the other half contains hydroxyl groups, making it super hydrophilic.
• Several molecules cluster together with alkene backbones, creating a tunnel in the cell membrane.
• Amphotericin B binds to ergosterol, the fungal equivalent of cholesterol.

Gramicidin A

• Gramicidin A is an antibiotic.
• It is a peptide composed of 15 amino acids.
• Gramicidin A is thought to coil into a helix with a hydrophobic exterior to interact with membrane lipids.
• The interior contains hydrophilic groups, allowing passage of ions through the lipid membrane.

Valinomycin

• Valinomycin is an antibiotic that acts as an ion carrier.
• It has a cyclic structure with 12 components of four different.
• Its structure contains alternating amide and ester bonds.
• Polar carbonyl groups face inside the ring while hydrophobic R groups face outside.
• Valinomycin is the perfect size to transport potassium (K+) ions across the cell membrane.
• Disrupting the ionic equilibrium in the cell.