Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A plant-derived morphinan as a novel lead compound active against malaria liver stages
PLoS Medicine, Volume 3, No. 12, Year 2006
Notification
URL copied to clipboard!
Description
Background: The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. Methods and Findings: Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 μM, TI 46, and IC 50 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. Conclusions: A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs. © 2006 Carraz et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC1716192/bin/pmed.0030513.sg001.ppt
https://efashare.b-cdn.net/share/pmc/articles/PMC1716192/bin/pmed.0030513.sg002.ppt
https://efashare.b-cdn.net/share/pmc/articles/PMC1716192/bin/pmed.0030513.st001.ppt
Authors & Co-Authors
Carraz, Maëlle
France, Paris
Museum National D'histoire Naturelle
France, Paris
Inserm
France, Paris
Sorbonne Université
Jossang, Akino
France, Paris
Museum National D'histoire Naturelle
Franetich, Jean François
France, Paris
Inserm
France, Paris
Sorbonne Université
Siau, Anthony
France, Paris
Inserm
France, Paris
Sorbonne Université
Cicéron, Liliane
France, Paris
Inserm
France, Paris
Sorbonne Université
Hannoun, Laurent
France, Paris
Hôpital Universitaire Pitié Salpêtrière
Sauerwein, Robert W.
Netherlands, Nijmegen
Radboud University Medical Center
Frappier, François
France, Paris
Museum National D'histoire Naturelle
Rasoanaivo, Philippe
Madagascar, Antananarivo
Institut Malgache de Recherches Appliquees Antananarivo
Snounou, Georges
France, Paris
Museum National D'histoire Naturelle
Mazier, Dominique
France, Paris
Inserm
France, Paris
Sorbonne Université
France, Paris
Hôpital Universitaire Pitié Salpêtrière
Statistics
Citations: 67
Authors: 11
Affiliations: 6
Identifiers
Doi:
10.1371/journal.pmed.0030513
ISSN:
15491277
e-ISSN:
15491676
Research Areas
Health System And Policy
Infectious Diseases
Study Locations
Madagascar