Inhibition of intracellular replication by pyridinylimidazoles
OwnerTyler Curielinventor
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Abstract
Substituted pyridinylimidazoles SB203580 and SB202190 strongly inhibit replication and cause stage conversion from active tachyzoites to relatively dormant bradyzoites of the medically important, obligate intracellular parasite Toxoplasma gondii. The pyridinylimidazoles probably mediate these effects by acting on a presently unidentified homologue(s) of human p38-mitogen activated protein kinase present in the tachyzoites. SB203580 also significantly enhanced in vitro inhibition of T. gondii replication by the approved anti-Toxoplasma drug pyrimethamine. The pyridinylimidazoles and related compounds disclosed herein could thus be significant adjuncts to currently available therapies.
Claims17
A method of inhibiting intracellular replication of a parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:
- contacting cells infected with said parasite with a substituted pyridinylimidazole drug that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in said parasite, wherein said drug inhibits intracellular replication of said parasite in said cells.
A method of inhibiting intracellular replication of a parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:
- contacting cells infected with said parasite with SB203580 or SB202190, wherein said drug inhibits intracellular replication of said parasite in said cells.
A method of inhibiting intracellular replication of a parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:
- contacting cells infected with said parasite with a substituted pyridinylimidazole drug having at least one halogenated substituent, wherein said drug specifically inhibits mitogen activated protein kinases endogenous to said parasite whereby the intracellular replication of said parasite in said cells is inhibited.
A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:
- contacting cells infected with Toxoplasma gondii with SB203580 or SB202190, wherein SB203580 or SB202190 inhibits the intracellular replication of Toxoplasma gondii in said cells.
A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:
- contacting cells infected with Toxoplasma gondii with a combination of an anti-Toxoplasma drug and a substituted pyridinylimidazole drug having at least one halogenated substituent that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in Toxoplasma gondii, wherein treatment with said drug combination increases inhibition of intracellular Toxoplasma gondii replication in said cells in comparison to treatment with either said anti-Toxoplasma drug or said substituted pyridinylimidazole drug alone.
A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:
- contacting cells infected with Toxoplasma gondii with a combination of an anti-Toxoplasma drug and one of SB203580 or SB202190, wherein treatment with said drug combination increases inhibition of intracellular Toxoplasma gondii replication in said cells in comparison to treatment with any one of said anti-Toxoplasma drug, SB203580 or SB202190.
A method of treating an individual infected with Toxoplasma gondii, comprising the step of:
- administering in combination to said individual a pharmacologically effective dose of pyrimethamine and a substituted pyridinylimidazole drug having at least one halogenated substituent that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in Toxoplasma gondii, wherein treatment with said drug combination inhibits intracellular replication of Toxoplasma gondii in said individual.
A method of treating an individual infected with Toxoplasma gondii, comprising the step of:
- administering in combination to said individual a pharmacologically effective does of pyrimethamine and one of SB203580 or SB202190, wherein treatment with said drug combination inhibits intracellular replication if Toxoplasma gondii in said individual.
A method of inhibiting replication of a parasite, comprising the step of contacting said parasite with an inhibitor of p38 MAPK activation.
Dependencies are inferred from the claim text.