Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-9808458-B2
Publication Date
2017-11-07
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 in animals by administering an effective amount of a compound of formula I, defined by specific chemical structures for Q, Y, R1, and R2, as well as pharmaceuticals comprising such compounds optionally combined with other antimalarials. Methods of inhibiting a plasmodial surface anion channel (PSAC) of the parasite in animals are also included, where inhibition is achieved through these compounds targeting the parasite clag3 gene family. The clag3 genes encode proteins associated with PSAC activity, a channel essential for nutrient uptake by malaria parasites in infected erythrocytes.
The problem addressed is the lack of effective vaccines and increasing resistance of malaria parasites to existing antimalarial drugs such as chloroquine. PSAC plays a central role in parasite nutrition by increasing erythrocyte permeability to nutrients but differs functionally and pharmacologically from human ion channels, providing a novel target. Existing antimalarials do not effectively inhibit PSAC, and resistance often arises from drug extrusion mechanisms. The invention aims to discover new therapeutics that specifically inhibit PSAC, overcoming drug resistance and providing alternative mechanisms to treat or prevent malaria.
The invention comprises compounds of formula I with defined substituents designed to inhibit PSAC by targeting clag3 gene family products. Pharmaceutical compositions include these compounds alone or in combination with other antimalarials, such as compounds of formulas II, V, and VI. The compounds possess high affinity and specificity for the PSAC ion channel, low cytotoxicity, novel chemical structures distinct from existing therapeutics, and drug-like features. Additionally, clag3 amino acid sequences, nucleic acids, vectors, host cells, populations of cells, antibodies, and compositions are provided to stimulate immune responses against the parasite's surface anion channel, contributing to malaria treatment or prevention.
Claims Coverage
The patent includes two independent claims focused on methods of treating malaria and inhibiting plasmodial surface anion channels using compounds of formula (I).
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 defined as Q-Y-R1-R2, where Q is a dioxo heterocyclyl ring fused to an aryl group optionally substituted with various groups, Y is SO2, R1 is optionally substituted piperazinyl, and R2 is optionally substituted aryloxyalkyl, including pharmaceutically acceptable salts.
Use of compounds of formula (I) for inhibiting plasmodial surface anion channels
A method of inhibiting a plasmodial surface anion channel of a parasite in an animal by administering an effective amount of a compound Q-Y-R1-R2 as described, where Q is a dioxo heterocyclyl ring fused to an aryl group optionally substituted, Y is SO2, R1 is optionally substituted piperazinyl, and R2 is optionally substituted aryloxyalkyl, including pharmaceutically acceptable salts.
Optional substituents for Q, R1, and R2
Specifications on the possible substitutions of Q (dioxotetrahydroquinoxalinyl), R1 (piperazinyl), and R2 (aryloxyalkyl), each optionally substituted with diverse substituents such as halo, hydroxy, alkyl, amino, carboxy, carbony, ureido, and others.
Combination therapy with other antimalarials
The method may further comprise administering at least one other antimalarial compound, including compounds of formulas II, V, and VI, such as artemisinin, mefloquine, or chloroquine, in combination with the compound of formula I.
Use in humans
The methods cover administration to animals including humans, and specifically to humans for treatment or inhibition of malaria or plasmodial surface anion channels.
The independent claims encompass methods of treating malaria and inhibiting plasmodial surface anion channels in animals by administering specific compounds of formula I characterized by a dioxo heterocyclyl aryl-fused group, a sulfone linker, piperazinyl and aryloxyalkyl substituents, optionally substituted with various functional groups. The claims also cover combination therapies with other antimalarials and include use in humans.
Stated Advantages
High affinity for the plasmodial surface anion channel (PSAC).
High specificity for the PSAC, reducing off-target effects.
Low or no cytotoxicity, supporting safety in treatment.
Chemical structures distinct from existing antimalarials, offering novel mechanisms of action.
Drug-like features supporting pharmaceutical development and use.
Documented Applications
Treatment or prevention of malaria in animals including humans by administering compounds of formula I.
Inhibition of plasmodial surface anion channels of parasites to block nutrient uptake necessary for parasite survival.
Use of pharmaceutical compositions comprising compounds of formula I in combination with other antimalarial compounds for enhanced therapeutic effect.
Stimulation of immune responses against plasmodial surface anion channels using clag3 amino acid sequences, nucleic acids, vectors, host cells, populations of cells, antibodies, or pharmaceutical compositions.
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