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Basore K, Cheng Y, Kushwaha AK, et al. How do antimalarial drugs reach their intracellular targets?. Front Pharmacol. 2015;6:91doi: 10.3389/fphar.2015.00091.
Basore, K., Cheng, Y., Kushwaha, A. K., Nguyen, S. T., & Desai, S. A. (2015). How do antimalarial drugs reach their intracellular targets?. Frontiers in pharmacology, 691. https://doi.org/10.3389/fphar.2015.00091
Basore, Katherine, et al. "How do antimalarial drugs reach their intracellular targets?." Frontiers in pharmacology vol. 6 (2015): 91. doi: https://doi.org/10.3389/fphar.2015.00091
Basore K, Cheng Y, Kushwaha AK, Nguyen ST, Desai SA. How do antimalarial drugs reach their intracellular targets?. Front Pharmacol. 2015 May 05;6:91. doi: 10.3389/fphar.2015.00091. eCollection 2015. PMID: 25999857; PMCID: PMC4419668.
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Front Pharmacol. 2015 May 05;6:91. doi: 10.3389/fphar.2015.00091. eCollection 2015.

How do antimalarial drugs reach their intracellular targets?.

Frontiers in pharmacology

Katherine Basore, Yang Cheng, Ambuj K Kushwaha, Son T Nguyen, Sanjay A Desai

Affiliations

  1. The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD, USA.
  2. Microbiotix Inc. , Worcester, MA, USA.

PMID: 25999857 PMCID: PMC4419668 DOI: 10.3389/fphar.2015.00091

Abstract

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.

Keywords: antimalarials; drug absorption; drug uptake; lipid diffusion of drugs; plasmodial surface anion channel; plasmodium falciparum

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