Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-9320786-B2
Publication Date
2016-04-26
Expiration Date
2032-04-11
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Abstract
The invention provides methods of treating or preventing malaria comprising administering to an animal an effective amount of a compound of formula (I): Q-Y—R1—R2 (I), wherein Q, Y, R1, and R2 are as described herein. Methods of inhibiting a plasmodial surface anion channel of a parasite in an animal are also provided. The invention also provides pharmaceutical compositions comprising a compound represented by formula (I) in combination with any one or more compounds represented by formulas II, V, and VI. Use of the pharmaceutical compositions for treating or preventing malaria or for inhibiting a plasmodial surface anion channel in animals including humans are also provided. Also provided by the invention are clag3 amino acid sequences and related nucleic acids, vectors, host cells, populations of cells, antibodies, and pharmaceutical compositions.
Core Innovation
The invention provides methods of treating or preventing malaria by administering to an animal an effective amount of compounds of formula (I), wherein Q, Y, R1, and R2 define specific groups and substitutions. These compounds inhibit a plasmodial surface anion channel (PSAC) of a parasite in an animal. Pharmaceutical compositions combining compounds of formula (I) with other antimalarial compounds represented by formulas II, V, and VI are also provided for treating or preventing malaria or for inhibiting PSAC in animals including humans.
Malaria is caused by Plasmodium parasites and remains a leading cause of death worldwide, with existing treatments limited by drug resistance and no effective vaccine. The problem addressed is the need for new antimalarial agents due to resistance to current drugs. PSAC is a molecular mechanism that increases infected red blood cell permeability and plays a central role in parasite nutrient acquisition. The invention targets this channel using novel compounds that have high affinity and specificity for PSAC, offering a new therapeutic approach.
The invention also provides clag3 amino acid sequences, related nucleic acids, vectors, host cells, antibodies, and pharmaceutical compositions, which can stimulate an immune response against PSAC of a parasite. Methods of stimulating such immune responses by administering these components are included. Embodiments of the compounds possess advantages such as differing chemical structures from existing antimalarials, low cytotoxicity, and drug-like features. The disclosed compounds and compositions inhibit PSAC and have been shown to inhibit parasite growth, especially under nutrient-limiting conditions.
Claims Coverage
The patent contains two independent claims directed to methods of treating malaria and inhibiting the plasmodial surface anion channel by administering compounds of formula (I), each featuring specific chemical moieties.
Use of compounds of formula (I) for treating malaria
A method of treating malaria in an animal by administering an effective amount of a compound of formula (I) where Q is a heterocyclic amido group linked to a heterocyclic group optionally substituted with various functional groups, Y is SO2, R1 is piperazinyl optionally substituted similarly, and R2 is aryl optionally substituted similarly, or a pharmaceutically acceptable salt thereof.
Use of compounds of formula (I) for inhibiting plasmodial surface anion channel
A method of inhibiting the plasmodial surface anion channel of a Plasmodium parasite by administering an effective amount of a compound of formula (I) having the same group definitions as above, or a pharmaceutically acceptable salt thereof.
The claims focus on methods of treating malaria and inhibiting PSAC activity by administering specific compounds of formula (I) characterized by the chemical groups Q, Y, R1, and R2, with particular substitutions. The inventive features cover the chemical composition of these compounds and their use in malaria treatment and PSAC inhibition, including combinations with other antimalarial compounds.
Stated Advantages
High affinity for the plasmodial surface anion channel.
High specificity for the PSAC, reducing off-target effects.
Low or no cytotoxicity, improving safety in treatment.
A chemical structure distinct from existing antimalarial drugs, providing a novel mechanism of action.
Drug-like properties amenable to pharmaceutical development.
Documented Applications
Treatment or prevention of malaria in animals including humans by administering compounds of formula (I).
Inhibition of plasmodial surface anion channel activity in parasites infecting animals including humans.
Pharmaceutical compositions combining compounds of formula (I) with one or more antimalarial compounds for enhanced treatment or prevention of malaria.
Use of clag3 amino acid sequences, nucleic acids, vectors, host cells, and antibodies to stimulate immune responses against Plasmodium parasites.
Use of PSAC inhibitors to study and select for parasite clones with altered clag3 expression or channel activity.
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