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

Author

Listed:
  • Grazia Camarda

    (Liverpool School of Tropical Medicine)

  • Piyaporn Jirawatcharadech

    (Liverpool School of Tropical Medicine)

  • Richard S. Priestley

    (Liverpool School of Tropical Medicine
    University of Oxford)

  • Ahmed Saif

    (Liverpool School of Tropical Medicine
    Najran University)

  • Sandra March

    (Massachusetts Institute of Technology)

  • Michael H. L. Wong

    (University of Liverpool)

  • Suet Leung

    (University of Liverpool)

  • Alex B. Miller

    (Massachusetts Institute of Technology)

  • David A. Baker

    (London School of Hygiene & Tropical Medicine)

  • Pietro Alano

    (Istituto Superiore di Sanità)

  • Mark J. I. Paine

    (Liverpool School of Tropical Medicine)

  • Sangeeta N. Bhatia

    (Massachusetts Institute of Technology)

  • Paul M. O’Neill

    (University of Liverpool)

  • Stephen A. Ward

    (Liverpool School of Tropical Medicine)

  • Giancarlo A. Biagini

    (Liverpool School of Tropical Medicine)

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.

Suggested Citation

  • Grazia Camarda & Piyaporn Jirawatcharadech & Richard S. Priestley & Ahmed Saif & Sandra March & Michael H. L. Wong & Suet Leung & Alex B. Miller & David A. Baker & Pietro Alano & Mark J. I. Paine & Sa, 2019. "Antimalarial activity of primaquine operates via a two-step biochemical relay," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11239-0
    DOI: 10.1038/s41467-019-11239-0
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