Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-12059418-B2
Publication Date
2024-08-13
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 an effective amount of a compound of formula I, wherein Q, Y, R1, and R2 are defined chemical groups as detailed in the patent. These compounds inhibit a plasmodial surface anion channel (PSAC) of the parasite in an animal, including humans. Pharmaceutical compositions comprising a compound of formula I in combination with additional antimalarial compounds are also provided. The invention further includes clag3 amino acid sequences, related nucleic acids, vectors, host cells, populations of cells, antibodies, and pharmaceutical compositions, which can stimulate an immune response against the PSAC.
Malaria, transmitted by mosquitoes and caused by Plasmodium parasites, remains a leading cause of death globally, especially in children under five. There is no effective vaccine currently, and resistance to existing antimalarial drugs necessitates new treatments. The plasmodial surface anion channel (PSAC) alters red blood cell permeability to nutrients essential for parasite survival. PSAC shows unique electrophysiological properties and allows nutrient uptake while excluding Na+ to prevent osmotic lysis of infected red blood cells. The invention addresses the problem of drug-resistant malaria by targeting PSAC to inhibit parasite nutrient acquisition, thereby treating or preventing malaria.
The invention also identifies clag3.1 and clag3.2 genes as encoding the parasite PSAC, with evidence supported by genetic crosses, allele-specific expression, and complementation experiments. Methods include administering compounds of formula I to modulate or inhibit PSAC function, impairing parasite growth. Additionally, variants such as chimeric clag3.1/clag3.2 genes and antibodies targeting clag3 sequences are provided for treatment or prevention of malaria and for stimulating immune responses.
Claims Coverage
The patent includes multiple independent claims covering pharmaceutical compositions comprising compounds of formula I and their combinations with other antimalarials. The inventive features relate to the specific chemical structures, combinations, and therapeutic uses of these compounds.
Pharmaceutical composition with specific compound of formula I and antimalarial
The composition comprises a compound of formula I, where Q is a heterocyclic amido group linked to a heterocyclic group optionally substituted with various groups; Y is SO2; R1 is optionally substituted piperidinyl; and R2 is optionally substituted aryloxyalkyl; or a pharmaceutically acceptable salt thereof, combined with at least one other antimalarial compound.
Combination with other antimalarial compounds
The composition additionally includes at least one other antimalarial compound selected from compounds represented by formulas II, V, and VI or their pharmaceutically acceptable salts, providing combination therapies for malaria treatment or prevention.
Use of specific chemical moieties in the composition
Claims specify particular selections of Q, R1, and R2 groups within formula I, defining structural variants of the compounds for use in pharmaceutical compositions.
Use of compound of formula II and VI in combination
Specific compounds of formulas II and VI are recited as components of combinations with compounds of formula I, enhancing antimalarial efficacy.
Pharmaceutical composition comprising ISG-23 or its salt
The composition comprises the compound ISG-23 or a pharmaceutically acceptable salt thereof, defining a distinct compound within the scope of the invention.
The independent claims broadly cover pharmaceutical compositions comprising compounds of formula I with defined chemical groups, alone or combined with other antimalarials such as compounds of formulas II, V, and VI, for use in treating or preventing malaria and inhibiting plasmodial surface anion channels.
Stated Advantages
High affinity for the plasmodial surface anion channel.
High specificity for the ion channel.
Low or no cytotoxicity.
Chemical structures different from existing antimalarials.
Drug-like features enhancing therapeutic potential.
Ability to inhibit parasite nutrient acquisition by targeting PSAC.
Capability to treat or prevent malaria including drug-resistant strains by a novel mechanism.
Documented Applications
Treatment or prevention of malaria by administering compounds of formula I to animals, including humans.
Inhibition of plasmodial surface anion channels of parasites in animals to block nutrient uptake and parasite growth.
Use of pharmaceutical compositions combining formula I compounds with other antimalarial compounds for enhanced efficacy.
Use of clag3 amino acid sequences, nucleic acids, vectors, host cells, populations of cells, and antibodies to stimulate immune responses against malaria parasites.
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