Parasites Plasmodium Falciparum

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 2002, 419, 498-511. 

Francis, S. Sullivan, D. J. Goldberg, D. E. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu. Rev. Microbiol. 1997, 51, 97-123. 

Gardner M), Tettelin H, Carucci DJ et al. Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. Science 1998 282[5391] 1126 1132. Hoffman SL, Rogers WO, Carucci DJ, Venter JC. From genomics to vaccines malaria as a model system. Nature Med 1998 4[12] 1351—1353. 

A simple assay for the detection of the malarial parasite Plasmodium falciparum involves saponin lysis of blood sample and membrane filtration followed by amplification of the consensus sequence of eight 21-bp repeats. This procedure has been successfully used in the field (F2). A PCR assay targeting kinetoplast DNA sequences of Leishmania species was also successfully tested in the field (F2). Molecular methods for the detection of toxoplasma gondii and several other parasites have been reviewed (F2). 

Chen M, Theander TG Christensen SB, Hviid L, Zhai L, Kharazmi A. (1994) Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii mitctxon. Antimicrob Agents Chemother 38 1470-1475. 

Chloroquine is a rapidly acting blood schizonti-cide with some gametocytocidal activity. It is used with primaquine for Plasmodium vivax and Plasmodium ovale infections. It has been widely used prophylactically by traveler s to endemic areas. Its mechanism of action is unclear. It is believed to hinder the metabolism of hemoglobin in the parasite. Presumably chloroquine prevents the formation in the plasmodia of polymers out of free heme which then builds up and becomes toxic. Resistance occurs as a consequence of the expression of a membrane phospho-glycoprotein pump in the plasmodia which is able to expel chloroquine from the parasite. Plasmodium falciparum is the most likely to become resistant. 

It has been established that DXS catalyzes the first step in a novel biosynthetic pathway leading to isoprenoids in bacteria, algae, plant chloroplasts, and in the malaria parasite, Plasmodium falciparum. DXS is therefore a novel target for antibiotics, herbicides, or anti-malarials. Our work has contributed to an understanding of the novel biosynthetic pathway and could further open new perspectives on how to inhibit the pathway in pathogenic bacteria, protists, or weeds. 

Krungkrai SR, Learngaramkul P, Kudan S, Prapunwattana P, Krungkrai JP (1999) Mitochondrial heterogeneity in human malarial parasite Plasmodium falciparum. Science Asia 25 77-83... 

Figure 5-42 Intact DNA from the chromosomes of three strains of the malaria parasite Plasmodium falciparum, ranging from 750 Kb to 5 Mb, separated by pulsed-field gel electrophoresis. Courtesy of C. Smith and T. E. Wellems. Reproduced by permission of Amersham Pharmacia Biotech Inc.

Nirmalan, N., Sims, P.F.C. and Hyde, J.E. (2004) Quantitative proteomics of the human malaria parasite Plasmodium falciparum and its application to studies of development and inhibition. Molecular Microbiology 52, 11 87-11 99. 

Intracellular protozoa of the phylum Apicomplexa such as plasmodium, toxoplasma, and eimeria have long been known to respond to sulfonamides and sulfones. This has led to the assumption that Apicomplexa must synthesize their own folate in order to survive. The reaction of 2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine diphosphate with />aminobenzoate to form 7,8-dihydropteroate has been demonstrated in cell-free extracts of the human malaria parasite Plasmodium falciparum. 2-Amino-4-hydroxy-6-hydroxymethyl-dihydropteridine pyrophosphokinase and 7,8-dihydropteroate synthase have also been identified. Sulfathiazole, sulfaguanidine, and sulfanilamide act as competitive inhibitors of p-aminobenzoate. It has not been possible to demonstrate dihydrofolate synthase activity in the parasites, which raises the possibility that 7,8-dihydropteroate may have substituted for dihydrofolate in malaria parasites. Similar lack of recognition of folate as substrate was also observed in the dihydrofolate reductase of Eimeria tenella, a parasite of chickens. 

Lougovskoi, A.A., Okoyeh, N.J., and Chauhan, V.S. (1999) Mice immunised with synthetic peptide from N-terminal conserved region of merozoite surface antigen-2 of human malaria parasite Plasmodium falciparum can control infection induced by Plasmodium yoeliiyoelii 265BY strain. Vaccine 18(9-10), 920-930. 

QDO derivatives have been evaluated against the parasite Plasmodium falciparum (P. falciparum) responsible of Malaria and Trypanosoma cruzi (T. cruzi) responsible of American Trypanosomiasis. 

In the first model, we sought to reveal subgraphs of a biological interaction network that show substantial adaptations when cells transcriptionally respond to a changing environment or treatment. As a case study, we investigated the response of the malaria parasite Plasmodium falciparum to chloroquine and tetracycline treatments. 

Dahl EL, Shock JL, Shenai BR et al (2006) Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother 50(9) 3124-3131... 

Dorin D, Le Roch K, Sallicandro P et al (2001) Pfnek-1, a NIMA-related kinase from the hitman malaria parasite Plasmodium falciparum. Biochemical properties and possible involvement in MAPK regulation. Eur J Biochem 268(9/2600-2608... 

Dorin-Semblat D, Quashie N, Halbert J et al (2007) Functional characterization of both MAP kinases of the human malaria parasite Plasmodium falciparum by reverse genetics. Mol Microbiol 65(5/1170-1180... 

Dorin D, Alano P, Boccaccio I et al (1999) An atypical mitogen-activated protein kinase (MAPK) homologue expressed in gametocytes of the human malaria parasite Plasmodium falciparum. Identification of a MAPK signature. J Biol Chem 274(42 ) 29912-29920... 

Hicks KE, Read M, Holloway SP et al (1991) Glycolytic pathway of the human malaria parasite Plasmodium falciparum primary sequence analysis of the gene encoding 3-phosphoglycerate kinase and chromosomal mapping studies. Gene 100 123-129... 

Kanaani J, Ginsburg H (1989) Metabolic interconnection between the human malarial parasite Plasmodium falciparum and its host erythrocyte. Regulation of ATP levels by means of an adenylate translocator and adenylate kinase. J Biol Chem 264(6) 3194-3199... 

Ulschmid JK, Rahlfs S, Schirmer RH, Becker K (2004) Adenylate kinase and GTP AMP phosphotransferase of the malarial parasite Plasmodium falciparum. Central players in cellular energy metabolism. Mol Biochem Parasitol 136(2 ) 211-220... 

Ross-Macdonald PB, Graeser R, Kappes B et al (1994) Isolation and expression of a gene specifying a cdc2-like protein kinase from the human malaria parasite Plasmodium falciparum. Eur J Biochem 220(3) 693-701... 

Dorin D, Semblat JP, Poullet P et al (2005) PfPK7, an atypical MEK-related protein kinase, reflects the absence of classical three-component MAPK pathways in the human malaria parasite Plasmodium falciparum. Mol Microbiol 55(1 ) 184-196... 

Scientists at the University of Michigan Medical School, in collaboration with those at the Indian Institute of Science in Bangalore, have carried out tests on curcumin that show it to inhibit the drug-resist-ant forms of malaria and reported their findings in the Journal of Biological Chemistry in December 2004. Mice infected with the related parasite, Plasmodium falciparum, which causes rodent malaria, were fed curcumin and this reduced the number of parasites in the blood by as much as 90%, and completely protected more than a quarter of mice to whom it was given. Whether it could be a treatment for human malarial infection remains to be seen. 

With the Chinese claims validated in 1984 by Klayman and coworkers,94 studies in the early 1980s rapidly addressed two key issues with the advancement of artemisinin as an antimalarial drug. One, how could it be made commercially and if so, what is its mode of action Although the former question was addressed,95,96 the lack in understanding its activity was reported by Gu.97 Here, evidence from prior studies indicated that, while active analogues could be prepared, including dihydroartemisinin and artemether (Figure 3.8), the endoperoxide function was key to this activity.98 In their work, Gu and co-workers postulated that the activity arose from modification of protein synthesis within the malaria parasite, Plasmodium falciparum 1 This was followed by a series of studies that indicated that the activity of artemisinin was attenuated by addition... 

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