Plasmodial surface anion channel inhibitors for the treatment or prevention of malaria
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10265313-B2
Publication Date
2019-04-23
Expiration Date
2032-04-11
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 a compound of formula I defined by the structure Q-Y—R1—R2, where Q, Y, R1, and R2 are specific chemical groups described in detail. The compounds inhibit a plasmodial surface anion channel (PSAC) of the malaria parasite. Pharmaceutical compositions combining compounds of formula I with other antimalarial compounds are also provided. The invention further includes clag3 amino acid sequences and related nucleic acids, vectors, host cells, antibodies, and pharmaceutical compositions that can be used to treat or prevent malaria or stimulate immune responses against the PSAC.
Malaria remains a major infectious disease with serious health and economic impacts, and there is no effective vaccine currently available. Resistance to existing antimalarial drugs creates a need for novel treatments. The invention addresses this need by targeting PSAC, a unique ion channel expressed on infected red blood cells, which plays a central role in parasite nutrient acquisition and survival.
PSAC exhibits unique properties that distinguish it from human ion channels, including extraordinary selectivity and low permeability to Na+, which is critical to prevent osmotic lysis of infected cells. The parasite gene family clag3 encodes components of PSAC, and the invention proposes compounds that inhibit this channel, potentially by binding to polymorphic sites within clag3 gene products. This approach offers advantages, including high affinity and specificity for the channel, low cytotoxicity, and novel chemical structures different from existing antimalarials.
Claims Coverage
The patent contains two independent claims covering methods of treating malaria and methods of inhibiting a plasmodial surface anion channel using a compound of formula I.
Defined chemical structure for malaria treatment and PSAC inhibition
Use of compounds of formula I, where Q is a heterocyclic group fused to a heterocyclic amido group (optionally substituted), Y is sulfur, R1 is a benzo fused heterocyclyl (optionally substituted), and R2 is a heterocyclyl carbonylamino (optionally substituted), or pharmaceutically acceptable salts thereof, administered in an effective amount to an animal for treating malaria or inhibiting PSAC.
Use in combination with other antimalarial compounds
Administration of compounds of formula I together with at least one other antimalarial compound, including compounds of formulas II, V, and VI, for enhanced treatment or inhibition.
The independent claims cover chemical compounds with specified substituents for use in treating malaria or inhibiting plasmodial surface anion channels, including their use alone or in combination with other antimalarial agents.
Stated Advantages
High affinity for the plasmodial surface anion channel.
High specificity for the plasmodial surface anion channel.
No or low cytotoxicity.
Chemical structures distinct from existing antimalarial drugs.
Drug-like features improving therapeutic potential.
Exposed location of PSAC on infected red blood cells allowing direct drug access and reducing likelihood of resistance.
Improved parasite killing efficacy under nutrient-limited conditions, suggesting a novel mechanism of action via nutrient uptake inhibition.
Documented Applications
Treatment or prevention of malaria in animals, including humans, by administering compounds of formula I.
Inhibition of plasmodial surface anion channels to block parasite nutrient acquisition.
Stimulation of an immune response against the plasmodial surface anion channel of parasites using clag3 amino acid sequences, nucleic acids, vectors, host cells, antibodies, or pharmaceutical compositions.
Use of pharmaceutical compositions comprising compounds of formula I alone or in combination with other antimalarial compounds to treat or prevent malaria.
Interested in licensing this patent?