How do antimalarial drugs reach their intracellular targets?
Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at le...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-05-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00091/full |
| _version_ | 1819036868249911296 |
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| author | Katherine eBasore Yang eCheng Ambuj K. Kushwaha Son T. Nguyen Sanjay A. Desai |
| author_facet | Katherine eBasore Yang eCheng Ambuj K. Kushwaha Son T. Nguyen Sanjay A. Desai |
| author_sort | Katherine eBasore |
| collection | DOAJ |
| description | Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention. |
| first_indexed | 2024-12-21T08:12:21Z |
| format | Article |
| id | doaj.art-323409c4712b4201b0ec29c9720fc060 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T08:12:21Z |
| publishDate | 2015-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-323409c4712b4201b0ec29c9720fc0602022-12-21T19:10:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122015-05-01610.3389/fphar.2015.00091136202How do antimalarial drugs reach their intracellular targets?Katherine eBasore0Yang eCheng1Ambuj K. Kushwaha2Son T. Nguyen3Sanjay A. Desai4National Institutes of HealthNational Institutes of HealthNational Institutes of HealthMicrobiotixNational Institutes of HealthDrugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00091/fullAntimalarialsPlasmodium falciparumdrug absorptionDrug Uptakeplasmodial surface anion channellipid diffusion of drugs |
| spellingShingle | Katherine eBasore Yang eCheng Ambuj K. Kushwaha Son T. Nguyen Sanjay A. Desai How do antimalarial drugs reach their intracellular targets? Frontiers in Pharmacology Antimalarials Plasmodium falciparum drug absorption Drug Uptake plasmodial surface anion channel lipid diffusion of drugs |
| title | How do antimalarial drugs reach their intracellular targets? |
| title_full | How do antimalarial drugs reach their intracellular targets? |
| title_fullStr | How do antimalarial drugs reach their intracellular targets? |
| title_full_unstemmed | How do antimalarial drugs reach their intracellular targets? |
| title_short | How do antimalarial drugs reach their intracellular targets? |
| title_sort | how do antimalarial drugs reach their intracellular targets |
| topic | Antimalarials Plasmodium falciparum drug absorption Drug Uptake plasmodial surface anion channel lipid diffusion of drugs |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00091/full |
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