A plant-derived morphinan as a novel lead compound active against malaria liver stages

被引:48
作者
Carraz, Maeelle
Jossang, Akino
Franetich, Jean-Francois
Siau, Anthony
Ciceron, Liliane
Hannoun, Laurent
Sauerwein, Robert
Frappier, Francois
Rasoanaivo, Philippe
Snounou, Georges
Mazier, Dominique [1 ]
机构
[1] Univ Paris 06, Ctr Hosp Univ Pitie Salpetriere, U511, INSERM, Paris, France
[2] Museum Natl Hist Nat, Lab Chim & Biochim Subst Nat, F-75231 Paris, France
[3] Univ Paris 06, Fac Med Pitie Salpetriere, Paris, France
[4] Ctr Hosp Univ Pitie Salpetriere, AP HP, Serv Chirurg Digest Hepato bilio Pancreat & Trans, Paris, France
[5] Radboud Univ Nijmegen Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands
[6] Inst Malgache Rech Appl, Lab Pharmacognosie Appl Malad Infect, Antananarivo, Madagascar
[7] Museum Natl Hist Nat, Lab Parasitol Comparee & Modeles Expt, F-75231 Paris, France
[8] Ctr Hosp Univ Pitie Salpetriere, Assistance Publ Hop Paris, Paris, France
关键词
D O I
10.1371/journal.pmed.0030513
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu M, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 mu M, 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 mu M, TI 46, and IC50 42.4 mu M, 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.
引用
收藏
页码:2392 / 2402
页数:11
相关论文
共 31 条
[1]   Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children:: randomised controlled trial [J].
Alonso, PL ;
Sacarlal, J ;
Aponte, JJ ;
Leach, A ;
Macete, E ;
Milman, J ;
Mandomando, I ;
Spiessens, B ;
Guinovart, C ;
Espasa, M ;
Bassat, Q ;
Aide, P ;
Ofori-Anyinam, O ;
Navia, MM ;
Corachan, S ;
Ceuppens, M ;
Dubois, MC ;
Demoitié, MA ;
Dubovsky, F ;
Menéndez, C ;
Tornieporth, N ;
Ballou, WR ;
Thompson, R ;
Cohen, J .
LANCET, 2004, 364 (9443) :1411-1420
[2]   Calculation of liver-to-blood inocula, parasite growth rates, and preerythrocytic vaccine efficacy, from serial quantitative polymerase chain reaction studies of volunteers challenged with malaria sporozoites [J].
Bejon, P ;
Andrews, L ;
Andersen, RF ;
Dunachie, S ;
Webster, D ;
Walther, M ;
Gilbert, SC ;
Peto, T ;
Hill, AVS .
JOURNAL OF INFECTIOUS DISEASES, 2005, 191 (04) :619-626
[3]  
BOITEAU P, 1986, PRECIS MAT MED MALGA
[4]   CYANOHYDRIDOBORATE ANION AS A SELECTIVE REDUCING AGENT [J].
BORCH, RF ;
BERNSTEIN, MD ;
DURST, HD .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1971, 93 (12) :2897-+
[5]   QUANTITATIVE ASSESSMENT OF ANTI-MALARIAL ACTIVITY INVITRO BY A SEMIAUTOMATED MICRODILUTION TECHNIQUE [J].
DESJARDINS, RE ;
CANFIELD, CJ ;
HAYNES, JD ;
CHULAY, JD .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1979, 16 (06) :710-718
[6]   New approach for high-throughput screening of drug activity on Plasmodium liver stages [J].
Gego, A ;
Silvie, O ;
Franetich, JF ;
Farhati, K ;
Hannoun, L ;
Luty, AJF ;
Sauerwein, RW ;
Boucheix, C ;
Rubinstein, E ;
Mazier, D .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2006, 50 (04) :1586-1589
[7]   Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives [J].
Guan, J ;
Zhang, Q ;
Montip, G ;
Karle, JM ;
Ditusa, CA ;
Milhous, WK ;
Skillman, DR ;
Lin, AJ .
BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (03) :699-704
[8]   From genomics to vaccines: Malaria as a model system [J].
Hoffman, SL ;
Rogers, WO ;
Carucci, DJ ;
Venter, JC .
NATURE MEDICINE, 1998, 4 (12) :1351-1353
[9]  
Landau Irene, 1998, P401
[10]  
LEPERS JP, 1988, LANCET, V1, P586