Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10869865-B2
Publication Date
2020-12-22
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 to an animal, wherein formula I comprises specific structural elements Q, Y, R1, and R2, each defined with particular chemical groups and optional substituents. The invention also offers methods of inhibiting a plasmodial surface anion channel (PSAC) of a parasite in an animal, pharmaceutical compositions combining compounds of formula I with other antimalarial compounds (formulas II, V, and VI), as well as means to stimulate immune responses via clag3 amino acid sequences and related vectors, host cells, antibodies, and pharmaceutical forms.
The problem being addressed is malaria, a major infectious disease causing significant global morbidity and mortality, particularly in African children under five. Existing antimalarial treatments are losing efficacy due to parasite resistance, and no effective vaccine is currently available. The invention aims to provide new therapeutic agents targeting PSAC, a parasite-specific ion channel essential for nutrient uptake and parasite survival within erythrocytes. PSAC exhibits unique properties distinct from human channels, including high selectivity and a critical role in excluding sodium to prevent osmotic lysis.
The inventive approach targets the PSAC, which is encoded by the clag3 gene family. By specifically inhibiting PSAC through compounds of formula I, or by employing pharmaceutical compositions comprising these compounds, the invention seeks to disrupt parasite nutrient acquisition and growth. The invention further identifies the role of clag3 genes in PSAC functioning, demonstrates the ability to alter PSAC inhibitor affinity through genetic and epigenetic mechanisms, and provides sequences, nucleic acids, and antibodies useful for malaria treatment, prevention, or immune stimulation.
Claims Coverage
The patent discloses one independent claim related to a pharmaceutical composition comprising specific chemical compounds and their combinations.
Pharmaceutical composition containing a compound of formula I
The composition comprises a compound represented by formula I: Q-Y—R1—R2, wherein each of Q, Y, R1, and R2 are chemical groups as defined, or a pharmaceutically acceptable salt thereof.
Combination with other antimalarial compounds
The pharmaceutical composition further includes at least one other antimalarial compound selected from compounds of formulas II, V, and VI, each with defined structural features and optional substitutions.
Specific chemical substituents defining compound components
The claim specifies chemical substituents for Q (e.g., pyridazinyl heterocyclyl with optional substitutions), R1 (e.g., piperazinyl with optional substitutions), and R2 (e.g., aryl with optional substitutions). Specific examples of substituents and chemical structures for Q, R1, and R2 are included, defining the scope of the pharmaceutical composition.
The claims cover pharmaceutical compositions comprising compounds of formula I with defined chemical structures and their combinations with other antimalarial compounds, characterizing inventive features by specific chemical moieties and their substitutions, designed for use in treating or preventing malaria.
Stated Advantages
High affinity and specificity for the plasmodial surface anion channel (PSAC).
Low or no cytotoxicity toward mammalian cells.
Chemical structures distinct from existing antimalarials, providing novel drug-like features.
Pharmaceutical compositions can synergize by combining compounds with other antimalarial agents to enhance parasite killing.
Documented Applications
Treatment or prevention of malaria in animals, including humans.
Inhibition of the plasmodial surface anion channel of parasites to disrupt nutrient uptake.
Use of clag3 amino acid sequences, nucleic acids, vectors, host cells, or antibodies to treat malaria or stimulate immune responses against PSAC.
Pharmaceutical compositions containing compounds of formula I alone or in combination with other antimalarials for malaria treatment or prevention.
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