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BIOL3027 - Selective Toxicity > VJ - Antimalarials II > Flashcards

VJ - Antimalarials II Flashcards

1
Q

What is the RTS,S/AS01E Vaccine (Mosquirix®) for Plasmodium falciparum composed of? (3)

A
  • Fragment of the P. falciparum circumsporozoite protein (CSP)
  • Central repeat (R) region and C-terminal regions with T cell epitopes (T)
  • Fused to hepatitis B surface antigen (S)
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2
Q

How is the RTS,S vaccine expressed (2) and what is the role of the adjuvant (1)?

A
  • Expressed in yeast carrying hepatitis B “S” expression cassettes
  • Yeast synthesizes RTS and S polypeptides that co-assemble into mixed lipoprotein particles

Vaccine is administered with a chemical adjuvant (AS01E) to enhance the immune response

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3
Q

What is the mechanism of action for the RTS,S vaccine and what is its efficacy (2)?

A

M.O.S: Prevents infection by inducing high antibody titers that block the parasite from infecting the liver by inhibiting binding via CSP

  • Provides protection against clinical and severe malaria in African children
  • Achieves a 30% reduction in severe malaria cases
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4
Q

What is the next generation of malaria vaccines represented by R21/M? (2)

A
  • Contains a higher proportion of the circumsporozoite (CS) antigen
  • Utilizes a different adjuvant
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5
Q

What are the key details about targeting liver forms (hypnozoites) for radical cure using 8-aminoquinolines? (Bare info)

A

Drug Class: 8-aminoquinolines

Type: Tissue schizonticide

Targets:

  • Active against the exoerythrocytic stage of Plasmodium parasites
  • Effective against liver hypnozoites (dormant stage in P. ovale and P. vivax)

Clinical Importance:

  • Prevents relapse, which can occur weeks or years after the initial infection
  • Used in combination with chloroquine

Gametocyte Activity:

  • Active against gametocytes of all four Plasmodium species, helping to reduce the spread of infection

Mechanism of Action (MOA):

  • Hydroxylated metabolites (pro-drug) catalyze the generation of hydrogen peroxide (H₂O₂)
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6
Q

What are the key details about drugs used for chemoprophylaxis and acute attack? (3)

A

Combination Therapy:

  • Used to prevent resistance and enhance effectiveness

Targets:

  • Folate metabolism
  • Mitochondrial electron transport
  • Hem detoxification & reactive oxygen species

Antibiotics Used:

  • Doxycycline
  • Clindamycin
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7
Q

What is the folate metabolism pathway and how do drugs act on it?

A

Folate Metabolism Pathway:

  • PABA + Pteridine → Dihydropteroic Acid (DHP)
  • DHP → Dihydrofolate (DHF)
  • DHF → Tetrahydrofolate (THF)
  • THF → Nucleic Acids (DNA/RNA)

Inhibit folate synthesis, crucial for nucleic acid production in parasites

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8
Q

What are 3 key drugs (type and action) that act on folate metabolism?

A

Sulfadoxine:

  • Type: Sulfonamide.
  • Action: Inhibits dihydropteroate synthase; prevents DHP synthesis.

Pyrimethamine:

  • Type: Antimalarial.
  • Action: Inhibits dihydrofolate reductase (DHFR); prevents DHF to THF conversion.

Proguanil:

  • Type: Prodrug (metabolized to cycloguanil).
  • Action: Similar to pyrimethamine; inhibits DHFR.
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9
Q

What are the details about combination therapies for malaria treatment? (2)

A

Sulfadoxine-Pyrimethamine (Fansidar):

Provides synergistic effects for malaria treatment

Proguanil (with Atovaquone):

  • Effective for both prophylaxis and treatment
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10
Q

What are the key details about Proguanil and Dapsone?

A

Proguanil:

  • Type: Prodrug, converted to cycloguanil
  • Combination: Used with atovaquone for enhanced effectiveness

Dapsone:
Note: Effective but has too many side effects, limiting its use

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11
Q

What is the mechanism of action of Atovaquone? (5- bare info)

A

Target:

  • Electron Transport Chain

Action:

  • Acts as a competitive inhibitor of ubiquinone (UQ)
  • Inhibits mitochondrial electron transport at the cytochrome bc1 complex

Effects:

  • Collapses membrane potential
  • Leads to loss of mitochondrial function
  • May inhibit purine biosynthesis

Selective Toxicity:

  • Higher affinity for the parasite’s complex (IC50 in µM for parasites vs nM for human cells)

Efficacy:

  • Effective against many metabolizing stages of the parasite in both host and mosquito
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12
Q

What are the details about the combination therapy Malarone® (Proguanil/Atovaquone)? (2)

A

Components:

  • Atovaquone and proguanil (ratio 5:2)

Mechanism:

  • Act synergistically
  • Proguanil does not function as a dihydrofolate reductase inhibitor
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13
Q

What are the details about Quinine and its mechanism in inhibiting hem detoxification?

A

Target Blood Forms:

  • Drugs that inhibit hem detoxification (Quinolines)

Quinine:

  • Mechanism: Targets hem biocrystallization; accumulates in the Plasmodium digestive vacuole
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14
Q

What is the role of hemoglobin as a nutrient source during the erythrocytic stage of Plasmodium? (5-bare info)

A

Nutrient Source:

  • Hemoglobin is a major nutrient source during the intraerythrocytic asexual reproduction cycle

Digestion:

  • The parasite digests up to 80% of RBC hemoglobin for amino acids (catabolism)
  • Digestion occurs in the digestive vacuole, which has a low pH and contains proteases

Products:

  • Releases monomeric haem (ferriprotoporphyrin), peptides, and amino acids

Toxicity of Hem:

  • Hem is a pro-oxidant, catalyzing reactive oxygen species production (no haem oxygenase in Plasmodium)
  • Can bind to and disrupt cell membranes, damaging structures and causing lysis of host erythrocytes

Parasite Strategy:

  • Plasmodium has developed mechanisms to detoxify and remove the toxic haem
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15
Q

How does Plasmodium detoxify hem? (2)

A

Haem Detoxification:

  • Occurs through biocrystallization into hemozoin

Haem Detoxification Protein (HDP):

  • Converts toxic hem into ‘inert’ hemozoin crystals
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16
Q

What is the structure of hemozoin crystals? (2)

A
  • Comprised of haem dimers (hematin)
  • Form 2D crystals through hydrogen bonding between dimers
17
Q

How do drugs like chloroquine prevent hem biocrystallization and what are the effects? (3)

A

Mechanism:

  • Drugs like chloroquine inhibit the biocrystallization of haem
  • This inhibition prevents the detoxification of haem, leading to its accumulation

Effects:

  • Buildup of toxic haem increases oxidative stress within the parasite
  • Elevated levels of haem disrupt cellular structures, contributing to the lysis of host erythrocytes

Example:

  • Chloroquine: Primarily acts by preventing the conversion of toxic free haem into non-toxic hemozoin (the crystalline form), enhancing the toxicity to the Plasmodium parasite
18
Q

How does chloroquine accumulate in the Plasmodium digestive vacuole? (3)

A

Mechanism:

  • Chloroquine (CQ) accumulates in the Plasmodium digestive vacuole
  • Concentration increases from nanomolar (10⁻⁹ M) levels outside the parasite to millimolar (10⁻³ M) levels inside

pH Influence:

  • Protonation of exocyclic and ring nitrogens occurs due to the lower pH in the digestive vacuole (~pH 5.5) compared to the external environment (pH 7.4)
  • CQ has a pKa of around 8.5, causing it to be protonated in the acidic environment

Forms of CQ:

  • The deprotonated form of CQ is membrane permeable, allowing entry into the parasite
  • The charged (protonated) form cannot cross membranes, leading to accumulation within the digestive vacuole
19
Q

What are the semi-synthetic derivatives of artemisinin and their properties?

A

Artemisinin:

  • Parent compound with antimalarial properties

Artesunate:

  • Properties: Water-soluble, most active, and least toxic
  • Use: Often used in treatment due to its effectiveness and safety profile

Artemether:

  • Properties: Lipid-soluble, with the greatest half-life
  • Function: Crosses the blood-brain barrier (BBB), making it suitable for severe cases

Both artesunate and artemether are converted into the active metabolite dihydroartemisinin, which exerts the therapeutic effects against malaria.

20
Q

What is the proposed mechanism of action of artemisinin? (3)

A

Cleavage of Endoperoxide Bridge:

  • The endoperoxide bridge in artemisinin is cleaved by free heme or Fe²⁺
  • This reaction produces reactive oxygen species (ROS):

H₂O₂ + Fe²⁺ → Fe³⁺ + OH⁻

Effects:

  • Reactive species directly alkylate proteins, leading to protein malfunction

Additional Action:

  • Artemisinin acts as a direct inhibitor of phosphatidylinositol-3-kinase, which is involved in the stress response of the parasite
21
Q

What are artemisinin-based combination therapies (ACT) and their key features? (4)

A

Primary Treatment:

  • Used for symptomatic uncomplicated malaria (P. falciparum) (oral use)

Prophylaxis:

  • Not used for prophylaxis due to the short half-life of artemisinin

Mechanism:

  • Combines multiple drugs to target different pathways, reducing resistance

Example Combination:

  • Artesunate + Mefloquine: Increases oxidative stress on the parasite, affecting protein function and promoting hemozoin crystallization
22
Q

What is the mechanism of resistance to artemisinin? (2)

A

Mutation:

  • PfKelch13 C580Y mutation (along with ~20 other mutations) reduces binding affinity to PfPI3K

Mechanism of Resistance:

  • Increased levels of PfPI3K can overcome inhibition
  • Elevated PI3P levels may contribute to resistance
23
Q

What are the mechanisms of resistance to other antimalarials? (5)

A

Y268S Mutation:

  • Confers resistance to Atovaquone by affecting the cytochrome b (cytb) subunit of the cytochrome bc1 complex.

Bifunctional Dihydrofolate Reductase:

  • Resistance to Pyrimethamine and Cycloguanil.

Dihydropteroate Synthetase (pfDHPS):

  • Resistance to Sulfadoxine.

Multidrug Resistance Protein 1 (pfMDRP1):

  • Confers resistance to quinolines and various other drugs.

Chloroquine Resistance Transporter (pfCRT):

  • Associated with resistance to quinolines.
24
Q

What are the key features of Artefenomel (trioxane) in malaria treatment? (2)

A
  • Targets the same mechanisms as existing treatments but is more potent and specific.
  • Effective against resistant strains; potential for a single-dose cure.
25
Q

What is the role of the Piperaquine/Ferroquine combination in malaria treatment?

A

Enhances effectiveness through combination therapy

26
Q

What is the significance of the apicoplast in Plasmodium and its interaction with antibiotics? (3)

A
  • The apicoplast is an endosymbiotic organelle of algal origin.
  • Functions include fatty acid synthesis, isoprenoid synthesis, and possibly other metabolic processes.
  • Contains its own ribosomes, making it sensitive to doxycycline.
27
Q

What is the mechanism and role of doxycycline in malaria prophylaxis?

A

Currently the only prophylactic targeting the apicoplast in Plasmodium

Mechanism of Action:

  • Binds to the 30S ribosomal subunit of bacterial ribosomes
  • Prevents the attachment of aminoacyl-tRNA to the ribosome

BIOL3027 - Selective Toxicity (17 decks)

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