VJ - Antimalarials II Flashcards
What is the RTS,S/AS01E Vaccine (Mosquirix®) for Plasmodium falciparum composed of? (3)
- 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)
How is the RTS,S vaccine expressed (2) and what is the role of the adjuvant (1)?
- 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
What is the mechanism of action for the RTS,S vaccine and what is its efficacy (2)?
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
What is the next generation of malaria vaccines represented by R21/M? (2)
- Contains a higher proportion of the circumsporozoite (CS) antigen
- Utilizes a different adjuvant
What are the key details about targeting liver forms (hypnozoites) for radical cure using 8-aminoquinolines? (Bare info)
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)
What are the key details about drugs used for chemoprophylaxis and acute attack? (3)
Combination Therapy:
- Used to prevent resistance and enhance effectiveness
Targets:
- Folate metabolism
- Mitochondrial electron transport
- Hem detoxification & reactive oxygen species
Antibiotics Used:
- Doxycycline
- Clindamycin
What is the folate metabolism pathway and how do drugs act on it?
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
What are 3 key drugs (type and action) that act on folate metabolism?
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.
What are the details about combination therapies for malaria treatment? (2)
Sulfadoxine-Pyrimethamine (Fansidar):
Provides synergistic effects for malaria treatment
Proguanil (with Atovaquone):
- Effective for both prophylaxis and treatment
What are the key details about Proguanil and Dapsone?
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
What is the mechanism of action of Atovaquone? (5- bare info)
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
What are the details about the combination therapy Malarone® (Proguanil/Atovaquone)? (2)
Components:
- Atovaquone and proguanil (ratio 5:2)
Mechanism:
- Act synergistically
- Proguanil does not function as a dihydrofolate reductase inhibitor
What are the details about Quinine and its mechanism in inhibiting hem detoxification?
Target Blood Forms:
- Drugs that inhibit hem detoxification (Quinolines)
Quinine:
- Mechanism: Targets hem biocrystallization; accumulates in the Plasmodium digestive vacuole
What is the role of hemoglobin as a nutrient source during the erythrocytic stage of Plasmodium? (5-bare info)
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
How does Plasmodium detoxify hem? (2)
Haem Detoxification:
- Occurs through biocrystallization into hemozoin
Haem Detoxification Protein (HDP):
- Converts toxic hem into ‘inert’ hemozoin crystals
What is the structure of hemozoin crystals? (2)
- Comprised of haem dimers (hematin)
- Form 2D crystals through hydrogen bonding between dimers
How do drugs like chloroquine prevent hem biocrystallization and what are the effects? (3)
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
How does chloroquine accumulate in the Plasmodium digestive vacuole? (3)
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
What are the semi-synthetic derivatives of artemisinin and their properties?
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.
What is the proposed mechanism of action of artemisinin? (3)
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
What are artemisinin-based combination therapies (ACT) and their key features? (4)
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
What is the mechanism of resistance to artemisinin? (2)
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
What are the mechanisms of resistance to other antimalarials? (5)
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.
What are the key features of Artefenomel (trioxane) and Piperaquine / Ferroquinein malaria treatment? (2)
- Targets the same mechanisms as existing treatments but is more potent and specific.
- Effective against resistant strains; potential for a single-dose cure.
What is the role of the Piperaquine/Ferroquine combination in malaria treatment?
Enhances effectiveness through combination therapy
What is the significance of the apicoplast in Plasmodium and its interaction with antibiotics? (3)
- 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.
What is the mechanism and role of doxycycline in malaria prophylaxis?
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
