MK-4815
MK-4815 is an orally active small-molecule allosteric inhibitor of Falcilysin (FLN) with antimalarial activity. MK-4815 inhibits the viability of Plasmodium falciparum NF54 and Dd2 strains with IC50 values of 38 and 40 ng/mL, respectively. MK-4815 preferentially accumulates in erythrocytes containing mature trophozoite/schizont-stage parasites. MK-4815 preferentially binds to the partially closed conformation of FLN, shifting the FLN conformational equilibrium toward the partially closed state and restricting the hinge region-mediated transition from the partially closed state to the open state, thereby interfering with the catalytic cycle of FLN. MK-4815 can be used for malaria-related research.
For research use only. We do not sell to patients.
- CAS No.: 84210-35-5
- Formula: C15H25NO
- Molecular Weight:235.37
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
All Parasite Isoforms
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Biological Activity
Description
IC50 & Target
[2]|
Falcilysin |
In Vitro
MK-4815 (48 h) inhibits the viability of P. falciparum NF54 and Dd2 strains with IC50 values of 38 and 40 ng/mL, respectively[1].
MK-4815 (48 h) inhibits P. falciparum strains 3D7, K1, FCB, V1/S, FCR-3, and TM90 with IC50 values of 0.030, 0.004, 0.010, 0.007, 0.010, and 0.030 μg/mL, respectively[1].
MK-4815 (0.5 μg/mL; ring stage: 0.5-16 h; trophozoite/schizont stage: 1-16 h) has little effect on the viability of synchronized Dd2 ring-stage P. falciparum, but markedly inhibits late trophozoites/schizonts, with subsequent parasite growth reduced by approximately 25% after 1 h exposure and inhibition approaching 85% after 7 h exposure[1].
MK-4815 (up to 1.5 μM; 20 min; room temperature) accumulates in a dose-dependent manner in infected mouse erythrocytes enriched with mature trophozoite/schizont-stage P. berghei, whereas uptake in uninfected erythrocytes is extremely low; at the highest tested concentration of 1.5 μM, uptake remains unsaturated[1].
MK-4815 (20 min) accumulates substantially in human erythrocytes infected with mature trophozoite/schizont-stage P. falciparum, and this uptake is competitively inhibited by excess unlabeled MK-4815, whereas uptake in ring-stage-infected human erythrocytes and uninfected human erythrocytes is low[1].
Binding of MK-4815 to recombinant wild-type Falcilysin increases the thermal stability of FLN by 2.2°C[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
In Vivo
MK-4815 (12.5 mg/kg; p.o.; administered once on the day of infection, followed by twice daily dosing continued for 1, 2, 3, or 4 days; 3-9 doses in total) achieves 100% survival with no detectable parasitemia for up to 95 days post-infection in P. berghei-infected BALB/c mice using the 2.5-day regimen; in the 1.5-day regimen, 40% of mice remain parasite-free throughout the entire study period, while the remaining mice show prolonged survival to days 13, 15, and 21 post-infection, respectively[1].
MK-4815 (50 or 100 mg/kg; p.o.; single administration) shows complete in vivo efficacy in P. berghei-infected mice when administered on the day of infection[1].
MK-4815 (50 mg/kg; p.o.; single dose; administered 2-96 h post-infection) achieves 100% parasite-free survival in P. berghei-infected mice when administered no later than 48 h post-infection; when administration is delayed to 72 or 96 h, 40% of mice remain parasite-free at 107 days post-infection, and the remaining mice exhibit a survival extension of more than 10 days compared with the sham-treated group[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c (20 to 25 g; Taconic Farms)[1]
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Dosage:25 mg/kg; 12.5 mg/kg; 6.25 mg/kg; 3.13 mg/kg; 1.56 mg/kg
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Administration:p.o.; once on day of infection then twice daily for 4 additional days (total of nine treatments)
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Result:Achieved 100% survival in mice receiving 25, 12.5, or 6.25 mg/kg.
Cleared parasites completely for the duration of the study (74 days) at 25, 12.5, and 6.25 mg/kg.
Increased survival by approximately 10 days versus infected controls at 3.13 mg/kg.
Showed no significant efficacy at 1.56 mg/kg.
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Animal Model:BALB/c[1]
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Dosage:12.5 mg/kg
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Administration:p.o.; once on day of infection then twice daily for 1, 2, 3, or 4 additional days (total of three to nine treatments)
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Result:Achieved 100% survival with no detectable parasitemia for up to 95 days postinfection when treated for approximately 2.5 days.
Showed 40% of mice remained parasite free throughout the study when treated for 1.5 days.
Increased survival relative to controls (13, 15, and 21 days postinfection) in remaining mice treated for 1.5 days.
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Animal Model:BALB/c[1]
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Dosage:50, 100 mg/kg
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Administration:p.o.; single dose
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Result:Showed complete in vivo efficacy at both doses; data were reported without a displayed figure/table.
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Animal Model:BALB/c[1]
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Dosage:50 mg/kg
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Administration:p.o.; single dose at 24, 48, 72, or 96 h after infection
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Result:Provided full efficacy in animals treated following a 24- or 48-h delay.
Showed 40% of mice in the 72- and 96-h delayed-treatment groups were parasite free at 107 days postinfection.
Increased survival by approximately 10 days compared to sham-treated animals in remaining three mice in each delayed-treatment group.
Chemical Information
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CAS No. 84210-35-5
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Molecular Weight 235.37
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Formula C15H25NO
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SMILES
OC=1C=C(C=C(C1CN)C(C)(C)C)C(C)(C)C
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)