MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Antimalarial activity of primaquine operates via a two-step biochemical relay

Author(s)
March, Sandra; Miller, Alex B.; Bhatia, Sangeeta N.
Thumbnail
DownloadPublished version (1.337Mb)
Terms of use
Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/
Metadata
Show full item record
Abstract
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.
Date issued
2019-07
URI
https://hdl.handle.net/1721.1/125175
Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Camarda, Grazia et al. “Antimalarial activity of primaquine operates via a two-step biochemical relay.” Nature Communications 10 (2019): 3226 © 2019 The Author(s)
Version: Final published version
ISSN
2041-1723

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.