A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites
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Spry, Christina; Chai, Christina; Kirk, Kiaran; Saliba, Kevin
Description
The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B5). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the...[Show more]
dc.contributor.author | Spry, Christina | |
---|---|---|
dc.contributor.author | Chai, Christina | |
dc.contributor.author | Kirk, Kiaran | |
dc.contributor.author | Saliba, Kevin | |
dc.date.accessioned | 2015-12-13T22:58:44Z | |
dc.identifier.issn | 0066-4804 | |
dc.identifier.uri | http://hdl.handle.net/1885/83441 | |
dc.description.abstract | The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B5). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 μM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with Ki values in the nanomolar range. | |
dc.publisher | American Society for Microbiology | |
dc.source | Antimicrobial Agents and Chemotherapy | |
dc.subject | Keywords: coenzyme A; dexpanthenol; ethyl pantothenol; pantothenate kinase; pantothenic acid; pantothenic acid derivative; unclassified drug; article; concentration response; drug accumulation; drug efficacy; drug selectivity; drug structure; drug synthesis; host p | |
dc.title | A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.description.refereed | Yes | |
local.identifier.citationvolume | 49 | |
dc.date.issued | 2005 | |
local.identifier.absfor | 060502 - Infectious Agents | |
local.identifier.absfor | 060107 - Enzymes | |
local.identifier.absfor | 111501 - Basic Pharmacology | |
local.identifier.ariespublication | MigratedxPub11709 | |
local.type.status | Published Version | |
local.contributor.affiliation | Spry, Christina, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Chai, Christina, College of Physical and Mathematical Sciences, ANU | |
local.contributor.affiliation | Kirk, Kiaran, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Saliba, Kevin, College of Medicine, Biology and Environment, ANU | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 11 | |
local.bibliographicCitation.startpage | 4649 | |
local.bibliographicCitation.lastpage | 4657 | |
local.identifier.doi | 10.1128/AAC.49.11.4649-4657.2005 | |
dc.date.updated | 2015-12-12T07:24:09Z | |
local.identifier.scopusID | 2-s2.0-27644471425 | |
Collections | ANU Research Publications |
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