[Leish-l] Fwd: Articles found by RefScout 2006/03/22 2006/12

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This is RefScout-Newsletter 12/2006.

REQUEST: [ leishmaniasis ]

(10 articles match this request)

PMID: 16543933

TITLE: Genetic susceptibility to infectious disease: lessons from mouse models
of leishmaniasis.

AUTHORS: Marie LipoldovÃ¡, Peter Demant

AFFILIATION: Institute of Molecular Genetics, Academy of Sciences of the Czech
Republic, Fleming. nÃ¡m. 2, 166 37 Prague, Czech Republic.

REFERENCE: Nat Rev Genet 2006 Apr 7(4):294-305

Susceptibility to infectious disease is influenced by multiple host 
genes, most of which are low penetrance QTLs that are difficult to map 
in humans. Leishmaniasis is a well-studied infectious disease with a 
variety of symptoms and well-defined immunological features. Mouse 
models of this disease have revealed more than 20 QTLs as being 
susceptibility genes, studies of which have made important contributions
 to our understanding of the host response to infection. The functional 
effects of individual QTLs differ widely, indicating a networked 
regulation of these effects. Several of these QTLs probably also 
influence susceptibility to other infections, indicating that their 
characterization will contribute to our understanding of susceptibility 
to infectious disease in general.

PMID: 16448729

TITLE: Leishmania donovani: Identification of stimulatory soluble antigenic
proteins using cured human and hamster lymphocytes for their prophylactic
potential against visceral leishmaniasis.

AUTHORS: Ravendra Garg, Shraddha K Gupta, Parul Tripathi, K Hajela, S Sundar, S
Naik, Anuradha Dube

AFFILIATION: Division of Parasitology, Central Drug Research Institute, Lucknow,
India.

REFERENCE: Vaccine 2006 Apr 24(15):2900-9

Most of the studies for the identification of prophylactic antigens that
 elicit T cell responses were concentrated on membrane proteins of 
Leishmania donovani. This study was taken up to assess L. donovani 
soluble promastigote antigens for their ability to stimulate 
proliferation of peripheral blood mononuclear cells (PBMCs) from cured 
visceral leishmaniasis (VL) patients, endemic and non-endemic controls 
and lymphocytes/peritoneal macrophages of cured hamsters. The soluble 
protein was subjected to sequential precipitation with saturated 
ammonium sulphate (20%, 40%, 60% and 80%), of which largely 80% 
fractioned protein showed significant cellular responses in cured 
patients and hamsters. This fraction was further fractionated into five 
sub fractions by preparative SDS-PAGE and subjected to re-evaluation for
 their ability to induce cellular responses. Out of these, only F2 sub 
fraction belonging to the MW of 97.4-68kDa stimulated remarkable 
lymphoproliferative and IFN-gamma responses in cured VL patients and in 
endemic controls. Similarly, significant lymphoproliferative responses 
and nitric oxide production were also noticed in cured Leishmania 
infected animals indicating an element of uniformity in responses 
between hamster and human. F2 sub fraction, when evaluated for its 
prophylactic efficacy with BCG against L. donovani challenge in hamster 
exhibited significant parasite inhibition in spleen (71.1%; p<0.001) 
and liver (68.2%; p<0.001) as compared to their unvaccinated 
counterpart. The vaccinated animals showed significant 
lymphoproliferative response and nitric oxide production but leishmania 
specific IgG level were suppressed. The results indicate the presence of
 immunostimulatory and protective molecules in F2 sub fraction which may
 further be exploited for the development of a vaccine against VL, 
hitherto an unrealized goal.

PMID: 16455170

TITLE: Potential of KM+ lectin in immunization against Leishmania amazonensis
infection.

AUTHORS: Clarissa R Teixeira, Karen A Cavassani, Regis B Gomes, Maria Jania
Teixeira, Maria-Cristina Roque-Barreira, Benildo S Cavada, JoÃ£o Santana da
Silva, Aldina Barral, Manoel Barral-Netto

AFFILIATION: Centro de Pesquisas GonÃ§alo Moniz-Fiocruz and Faculdade de
Medicina da Bahia, Rua Waldemar FalcÃ£o 121, Salvador, BA 40295-001, Brazil.

REFERENCE: Vaccine 2006 Apr 24(15):3001-8

In the present study we evaluated Canavalia brasiliensis (ConBr), Pisum 
arvense (PAA) and Artocarpus integrifolia (KM+) lectins as 
immunostimulatory molecules in vaccination against Leishmania 
amazonensis infection. Although they induced IFN-gamma production, the 
combination of the lectins with SLA antigen did not lead to lesion 
reduction. However, parasite load was largely reduced in mice immunized 
with KM+ lectin and SLA. KM+ induced a smaller inflammatory reaction in 
the air pouch model and was able to inhibit differentiation of dendritic
 cells (BMDC), but to induce maturation by enhancing the expression of 
MHC II, CD80 and CD86. These observations indicate the modulatory role 
of plant lectins in leishmaniasis vaccination may be related to their 
action on the initial innate response.

PMID: 16517909

TITLE: First report of Leishmania infantum in French Guiana: canine visceral
leishmaniasis imported from the old world.

AUTHORS: Brice Rotureau, Christophe Ravel, Christine Aznar, Bernard Carme,
Jean-Pierre Dedet

AFFILIATION: Laboratoire Hospitalo-Universitaire de Parasitologie et Mycologie
MÃ©dicale, Equipe EA 3593, UFR de MÃ©decine de l'UniversitÃ© des Antilles et de
la Guyane, Campus Saint-Denis, B. P. 718, 97336 Cayenne, Guyane FranÃ§aise.
ufrmedag2 at wanadoo.fr

REFERENCE: J Clin Microbiol 2006 Mar 44(3):1120-2

The first two cases of canine visceral leishmaniasis in French Guiana 
are described. One infected dog was most probably imported from France. 
A second dog was then infected with Leishmania infantum in French Guiana
. These observations exemplify the intercontinental transportation 
theory for L. infantum.

PMID: 16517925

TITLE: Post-kala-azar dermal leishmaniasis due to Leishmania infantum in a human
immunodeficiency virus type 1-infected patient.

AUTHORS: D Stark, S Pett, D Marriott, J Harkness

AFFILIATION: Department of Microbiology, St. Vincent's Hospital, Darlinghurst
2010 NSW, Sydney, Australia. dstark at stvincents.com.au

REFERENCE: J Clin Microbiol 2006 Mar 44(3):1178-80

We report the first case of post-kala-azar dermal leishmaniasis due to 
Leishmania infantum in a human immunodeficiency virus type 1-infected 
patient in Australia. Molecular characterization of the isolate was 
performed using PCR restriction fragment length polymorphism targeting 
both repetitive sequences from Leishmania nuclear DNA and repetitive 
kinetoplast DNA minicircles for species differentiation.

PMID: 16300999

TITLE: Risk factors in the spread of leishmaniases: towards integrated
monitoring?

AUTHORS: Jean-Claude Dujardin

AFFILIATION: Institute of Tropical Medicine, Molecular Parasitology,
Nationalestraat 155, B-2000 Antwerpen, Belgium. jcdujard at itg.be

REFERENCE: Trends Parasitol 2006 Jan 22(1):4-6

Environmental changes, immune status and treatment failure constitute 
the three major risk factors for the (re-)emergence and spread of 
leishmaniases. Except for Leishmania-HIV co-infection, these risk 
factors are not systematically monitored and their interaction is poorly
 studied and understood. Recently, the multidisciplinary network Leish-
Med was launched to document this issue around the Mediterranean and to 
promote transborder control strategies.

PMID: 16398754

TITLE: Sero-epidemiological study of kala-azar in a village of Varanasi
district, India.

AUTHORS: R Kumar, K Pai, P Kumar, H P Pandey, S Sundar

AFFILIATION: Department of Biochemistry, Banaras Hindu University, Varanasi,
India. ramesh_1995 at sify.com

REFERENCE: Trop Med Int Health 2006 Jan 11(1):41-8

OBJECTIVE: To evaluate five kala-azar serological tests for field use. 
METHOD: Serological survey in Pandit Ka Purva village in Varanasi 
district, India, using Sia water test, aldehyde test, direct 
agglutination test (DAT), micro-enzyme-linked immunosorbent assay (ELISA
) and dot-ELISA. RESULTS: The total population of the village was 518, 
67 of whom showed typical clinical and parasitological features of kala-
azar, including seven who died. The age distribution of kala-azar cases 
showed significant differences, being highest among the 45-54-year age 
group. The disease was more prevalent among males. Serum samples were 
collected from 498 persons (96% of total population) including 67 kala-
azar cases and 40 disease controls (malaria, TB, leprosy, typhoid). Ten 
10 serum samples from healthy controls living in endemic area were also 
collected. The test sensitivities were: Sia water test, 85.0%; aldehyde 
test, 62.7%; DAT, 94.0%; micro-ELISA, 91.0% and dot-ELISA, 97.0%. The 
test specificities were: Sia water test 92.5%, aldehyde test, 93.2%, DAT
, 96.7; micro-ELISA, 97.6% and dot-ELISA, 98.4%. CONCLUSION: The dot-
ELISA is highly sensitive and specific, cheap, and easy to interpret 
with the naked eye, making it a powerful screening test for the 
surveillance and diagnosis of Indian kala-azar at field level.

PMID: 16506438

TITLE: Host preference of Phlebotomus argentipes and Phlebotomus papatasi in
different biotopes of West Bengal, India.

AUTHORS: A Palit, S K Bhattacharya, S N Kundu

AFFILIATION: National Institute of Cholera & Enteric Diseases (ICMR), Kolkata,
India.

REFERENCE: Int J Environ Health Res 2005 Dec 15(6):449-54

Host preference Phlebotomus argentipes and Phlebotomus papatasi in 
different biotopes was investigated in two highly endemic Kala-azar 
districts of West Bengal, India for a better understanding of the 
transmission dynamics. Blood meals of 304 P. argentipes and 206 P. 
papatasi, collected from different biotopes from two Kala-azar affected 
districts in West Bengal, were tested against seven different antisera 
by modified Ouchterlony gel diffusion techniques. It appeared that host 
preference of P. argentipes varied widely in different biotopes, which 
is mainly zoophilic (62.80%), preferring to feed on man as the second 
choice (24.92%); however it is also a "chance feeder" 
according to biotopes. Multiple blood meals are also prevalent in P. 
argentipes at a much higher rate than that of P. papatasi. The 
implication in relation to epidemiological significance has been 
discussed.

PMID: 16532694

TITLE: Characterization of Leishmania isolated from unhealed lesions caused by
leishmanization.

AUTHORS: S M H Hosseini, G R Hatam, S Ardehali

AFFILIATION: Department of Immunology, Razi Vaccine and Serum Research
Institute, Shiraz, Islamic Republic of Iran.

REFERENCE: East Mediterr Health J 2005 Jan-Mar 11(1-2):240-3

Leishmania parasites were isolated after 13 and 8 years from the 
unhealed lesions of 2 soldiers who had been immunized against 
leishmaniasis during the war between Iraq and the Islamic Republic of 
Iran. Isoenzyme characterization on these isolates using 11 enzyme 
systems was carried out and the results were compared with the enzyme 
profiles of the original isolates of L. major used for leishmanization. 
Minor enzymatic differences in glucose-6-phosphate dehyrognase and 
phosphoglucomutase were observed but otherwise the strains appeared 
unchanged.

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PMID: 15844420

TITLE: Autochthonous visceral leishmaniasis in dogs in North America.

AUTHORS: Peter M Schantz, Francis J Steurer, Zandra H Duprey, Katherine P
Kurpel, Stephen C Barr, Joan E Jackson, Edward B Breitschwerdt, Michael G Levy,
J C Fox

AFFILIATION: CDC, Division of Parasitic Diseases, National Center For Infectious
Diseases, 4770 Buford Hwy, Atlanta, GA 30341, USA.

REFERENCE: J Am Vet Med Assoc 2005 Apr 226(8):1316-22

REQUEST: [ leishmania ]

(16 articles match this request. 5 articles matching other requests removed)

PMID: 16533268

TITLE: Electron micrographic study of the removal of Leishmania from blood
products by leukodepletion filters.

AUTHORS: Lisa J Cardo, Ludmila Asher

AFFILIATION: From the Department of Blood Research, Transfusion Medicine Branch,
Walter Reed Army Institute of Research, Silver Spring, Maryland.

REFERENCE: Transfusion 2006 Mar 46(3):315-6

PMID: 16423830

TITLE: Leishmania major Expresses a Single Dihydroxyacetone Phosphate
Acyltransferase Localized in the Glycosome, Important for Rapid Growth and
Survival at High Cell Density and Essential for Virulence.

AUTHORS: Rachel Zufferey, Choukri Ben Mamoun

AFFILIATION: Department of Genetics and Developmental Biology and the Department
of Molecular, Microbial and Structural Biology, University of Connecticut Health
Center, Farmington, Connecticut 06030-3301.

REFERENCE: J Biol Chem 2006 Mar 281(12):7952-9

Despite major advances in the understanding of pathogenesis of the human
 protozoan parasite Leishmania major, little is known about the enzymes 
and the primary precursors involved in the initial steps of synthesis of
 its major glycerolipids including those involved in virulence. We have 
previously demonstrated that the initial step of acylation of the 
precursor glycerol 3-phosphate is not essential for the synthesis of 
ester and ether phospholipids in this parasite. Here we show that 
Leishmania expresses a single acyltransferase with high specificity for 
the precursor dihydroxyacetone phosphate and shows the best activity in 
the presence of palmitoyl-CoA. We have identified and characterized the 
LmDAT gene encoding this activity. LmDAT complements the lethality 
resulting from the loss of both dihydroxyacetone phosphate and glycerol-
3-phosphate acyltransferase activities in yeast. Recombinant LmDAT 
exhibits biochemical properties similar to those of the native enzyme of
 the promastigote stage parasites. We show that LmDAT is a glycosomal 
enzyme and its loss in a Deltalmdat/Deltalmdat null mutant results in 
complete abrogation of the parasite dihydroxyacetone phosphate 
acyltransferase activity. Furthermore, lack of LmDAT causes a major 
alteration in parasite division during the logarithmic phase of growth, 
an accelerated cell death during stationary phase, and loss of virulence
. Together, our results demonstrate that LmDAT is the only 
dihydroxyacetone phosphate acyltransferase of the L. major localized in 
the peroxisome, important for growth and survival and essential for 
virulence.

PMID: 16534735

TITLE: Minor Alkaloids From Guatteria dumetorum with Antileishmanial Activity.

AUTHORS: Jhonny Edmith Correa, Carlos HernÃ¡n RÃos, Amparo Del Rosario
Castillo, Luz I Romero, Eduardo Ortega-BarrÃa, Phyllis D Coley, Thomas A
Kursar, Maria VerÃ³nica Heller, William H Gerwick, Luis Cubilla Rios

AFFILIATION: Laboratorio de BioorgÃ¡nica Tropical, Universidad de PanamÃ¡,
RepÃºblica de PanamÃ¡

REFERENCE: Planta Med 2006 Feb 72(3):270-2

Nine known alkaloids [(+)-isodomesticine ( 1), (+)-norisodomesticine ( 2
), (+)-nantenine ( 3), (+)-neolitsine ( 4), (+)-lirioferine ( 5), (+)- N
-methyllaurotetanine ( 6), (+)-norlirioferine ( 7), (+)-isoboldine ( 8) 
and (+)-reticuline ( 9)] were isolated from young leaves of Guatteria 
dumetorum. Their structures were confirmed by NMR, mass and UV spectral 
analysis and by comparison to literature data. The growth inhibitory 
activity of each alkaloid was determined against the parasite Leishmania
 mexicana. Compounds 1 - 4 all showed significant activity whereby 
potency increased when a methylenedioxy functionality was present, 
especially at the 1,2-positions.

PMID: 16310413

TITLE: Chemokines in host-parasite interactions in leishmaniasis.

AUTHORS: Maria Jania Teixeira, Clarissa Romero Teixeira, Bruno Bezerril Andrade,
Manoel Barral-Netto, Aldina Barral

AFFILIATION: Centro de Pesquisas GonÃ§alo Moniz, Fiocruz, Rua Waldemar FalcÃ£o
121, 40295-001 Salvador, Bahia, Brazil.

REFERENCE: Trends Parasitol 2006 Jan 22(1):32-40

Crucial to the defense against leishmaniasis is the ability of the host 
to mount a cell-mediated immune response capable of controlling and/or 
eliminating the parasite. Cell recruitment to the site of infection is 
essential to the development of the host cellular immune response. The 
process is controlled by chemokines, which are chemotactic cytokines 
produced by leukocytes and tissue cells.

PMID: 16442348

TITLE: Bothrops moojeni myotoxin-II, a Lys49-phospholipase A(2) homologue: An
example of function versatility of snake venom proteins.

AUTHORS: Rodrigo G StÃ¡beli, Saulo F Amui, Carolina D Sant'ana, Matheus G Pires,
Auro Nomizo, Marta C Monteiro, Pedro R T RomÃ£o, Renata Guerra-SÃ¡, Carlos A
Vieira, JosÃ© R Giglio, Marcos R M Fontes, Andreimar M Soares

AFFILIATION: Instituto de Pesquisas em Patologias Tropicais, IPEPATRO,
Universidade Federal de Rondonia, UNIR-RO, Brazil.

REFERENCE: Comp Biochem Physiol C Toxicol Pharmacol 2006 Mar-Apr
142(3-4):371-81

MjTX-II, a myotoxic phospholipase A(2) (PLA(2)) homologue from Bothrops 
moojeni venom, was functionally and structurally characterized. The MjTX
-II characterization included: (i) functional characterization (
antitumoral, antimicrobial and antiparasitic effects); (ii) effects of 
structural modifications by 4-bromophenacyl bromide (BPB), cyanogen 
bromide (CNBr), acetic anhydride and 2-nitrobenzenesulphonyl fluoride (
NBSF); (iii) enzymatic characterization: inhibition by low molecular 
weight heparin and EDTA; and (iv) molecular characterization: cDNA 
sequence and molecular structure prediction. The results demonstrated 
that MjTX-II displayed antimicrobial activity by growth inhibition 
against Escherichia coli and Candida albicans, antitumoral activity 
against Erlich ascitic tumor (EAT), human breast adenocarcinoma (SK-BR-3
) and human T leukemia cells (JURKAT) and antiparasitic effects against 
Schistosoma mansoni and Leishmania spp., which makes MjTX-II a promising
 molecular model for future therapeutic applications, as well as other 
multifunctional homologous Lys49-PLA(2)s or even derived peptides. This 
work provides useful insights into the structural determinants of the 
action of Lys49-PLA(2) homologues and, together with additional 
strategies, supports the concept of the presence of others "
bioactive sites" distinct from the catalytic site in snake venom 
myotoxic PLA(2)s.

PMID: 16539034

TITLE: Selective action of fluoroquinolones against intracellular amastigotes of
Leishmania (Viannia) panamensis in vitro.

AUTHORS: Ibeth C Romero, Nancy G Saravia, John Walker

REFERENCE: J Parasitol 2005 Dec 91(6):1474-9

We have demonstrated that fluoroquinolones, a class of antibacterial 
agents that act through inhibition of type II DNA topoisomerases, exert 
selective action against intracellular amastigotes of Leishmania (
Viannia) panamensis at concentrations that are achievable in vivo. Drug 
cytotoxicity assays employing the luciferase reporter gene revealed that
 intracellular amastigotes were 6.6- to 25.9-fold more sensitive than 
human macrophages (P < 0.05) to second-generation fluoroquinolones in
 vitro. The most selective agents (enoxacin and ciprofloxacin) exhibited
 2 orders of magnitude greater potency against parasites (50% effective 
dose [ED50] = 54.9-83.4 microM) than host cells (ED50 = 1,425-1,740 
microM). Linear regression analysis of ED50 data confirmed a complete 
lack of correlation (r = 0.001) between the relative drug sensitivities 
of parasites and host cells. A potential relationship between the 
structures of fluoroquinolones and their relative leishmanicidal 
activities was observed. The key substituents of the basic pyridone beta
-carboxylic acid nucleus accounting for enhanced antiparasite potency 
and selectivity appear to be a nitrogen at position 8 of the bicyclic 
nucleus (enoxacin), a cyclopropyl substituent at the R1 site (
ciprofloxacin), and linkage of the R1 and X8 groups by a CH3CHO bridge 
to form a tricyclic compound (ofloxacin). These findings support the 
potential of fluoroquinolones and derivatives as novel antileishmanials 
and encourage their clinical evaluation.

PMID: 16539040

TITLE: Molecular characterization of a human BRCA2 homolog in Leishmania
donovani.

AUTHORS: Smita Misra, Mack Hall, Gautam Chaudhuri

AFFILIATION: Division of Microbial Pathogenesis & Immune Response, Department of
Biomedical Sciences, Meharry Medical College, Nashville, Tennessee 37208, USA.

REFERENCE: J Parasitol 2005 Dec 91(6):1492-5

The breast cancer susceptibility protein BRCA2 is implicated in the DNA 
double-strand break (DSB) repair pathway through its association with 
Rad51. It is almost a ubiquitous eukaryotic protein; homologs of the 
BRCA2 gene (BRH2) have been identified in many mammals, as well as 
nonmammals. As a part of our quest to understand the DNA damage, repair
, and recombination process in the parasitic protozoan, Leishmania sp., 
we have cloned and characterized a BRCA2 homolog from Leishmania sp. (
LBRH2). LBRH2 is coded by a single-copy gene (ORF = 3,498 bp) located at
 the 700-kb chromosome 16. The transcripts in both the promastigotes and
 the amastigotes are approximately 3.9 kilonucleotides (knt) in size, 
corresponding to a protein with a calculated molecular mass of 128 kDa. 
The primary transcript of the gene is alternatively trans-spliced to 
produce 3 distinct mRNAs with altered folded structures at their 5' ends
. This study will contribute toward the understanding of a potential 
RAD51-mediated DNA recombination/repair pathway in Leishmania sp.

PMID: 16539044

TITLE: Molecular characterization of the hexokinase gene from Leishmania major.

AUTHORS: Perunthottathu K Umasankar, P Cyril Jayakumar, Yogesh S Shouche,
Millind S Patole

AFFILIATION: National Centre for Cell Science, University of Pune Campus, Ganesh
Khind, India.

REFERENCE: J Parasitol 2005 Dec 91(6):1504-9

The coding sequence for hexokinase enzyme was cloned from Leishmania 
major. The sequence was found to encode an enzyme with a molecular mass 
of 51.74 kDa. Amino acid sequence showed maximum homology with known 
trypanosome and plant hexokinases. It has a calculated isoelectric point
 of 8.46 and contains an N-terminal peroxisome-targeting signal, the 
characteristics frequently associated with glycosomal proteins. The 
sequence indicated the presence of conserved amino acid residues and 
motifs that are present in plant and mammalian hexokinases; these are 
apparently involved in the binding of different substrates. The L. major
 genome was found to have 2 copies of hexokinase coding sequences in 
tandem with an intergenic spacer of 2.58 kb. Both the genes in the 
hexokinase locus were transcribed as individual transcripts in a 
monocistronic form, having the same size as seen by Northern blot 
analysis. The hexokinase gene was transcribed in large amounts in the 
promastigote stage, whereas there is only weak expression in the 
amastigote stage as determined by RT-PCR analysis. Sequencing of 
hexokinase loci from different Leishmania species (e.g., L. donovani, L
. infantum, L. tropica, and L. mexicana) revealed that the hexokinase 
locus is highly conserved at the DNA and protein levels among species of
 Leishmania compared with trypanosomes.

PMID: 16310743

TITLE: Trypanosomatid biology and euglenozoan evolution: new insights and
shifting paradigms revealed through genome sequencing.

AUTHORS: Michael L Ginger

AFFILIATION: Sir William Dunn School of Pathology, University of Oxford, South
Parks Road, Oxford OX1 3RE, UK. michael.ginger at path.ox.ac.uk

REFERENCE: Protist 2005 Dec 156(4):377-92

PMID: 16535862

TITLE: Chemosensitizers in drug transport mechanisms involved in protozoan
resistance.

AUTHORS: Bruno Pradines, Jean-Marie PagÃ¨s, Jacques Barbe

AFFILIATION: UnitÃ© de Recherche en Biologie et Epidemiologie Parasitaires,
Institut de MÃ©decine Tropicale du Service de SantÃ© des ArmÃ©es, Marseille,
France.

REFERENCE: Curr Drug Targets Infect Disord 2005 Dec 5(4):411-31

The emergence and spread of antiparasitic drug resistance pose a severe 
and increasing public health threat. Failures in prophylaxis or those in
 treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic 
lactones, antifolate drugs, arsenic and antimony containing drugs 
sulfamides induce reemergence of parasitic-related morbidity and 
mortality. Resistance is often associated with alteration of drug 
accumulation into parasites, which results from a reduced uptake of the 
drug, an increased efflux or, a combination of the two processes. 
Resistance to quinolines, artemisinin derivatives and arsenicals and 
expression of an active efflux mechanism are more or less correlated in 
protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. 
Various parasite candidate genes have been proposed to be involved in 
drug resistance, each concerned in membrane transport. Genes encoding 
membrane glycoproteins, orthologue to the P-glycoproteins identified in 
MDR human cancer cells, have been described in these resistant pathogens
 in addition to various membrane proteins involved in drug transport. 
Several compounds have demonstrated, in the past decade, promising 
capability to reverse the drug resistance in parasite isolates in vitro
, in animal models and for human malaria. These drugs belong to 
different pharmacological classes such as calcium channel blockers, 
tricyclic antidepressants, antipsychotic calmodulin antagonists, 
histamine H1-receptor antagonists, analgesic antipyretic drugs, non-
steroidal anti-inflammatory drugs, and to different chemical classes 
such as synthetic surfactants, alkaloids from plants used in traditional
 medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene 
derivatives. Here, are summarized the molecular bases of antiparasitic 
resistance emphasizing recent developments with compounds acting on 
trans-membrane proteins involved in drug efflux or uptake.

PMID: 12107758

TITLE: Peptoid inhibition of trypanothione reductase as a potential
antitrypanosomal and antileishmanial drug lead.

AUTHORS: C Chan, H Yin, J H McKie, A H Fairlamb, K T Douglas

AFFILIATION: School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Oxford Road, Manchester M13 9PL, U.K.

REFERENCE: Amino Acids 2002 Jun 22(4):297-308

One route to the design of lead compounds for rational drug design 
approaches to developing drugs against trypanosomiasis, Chagas' disease 
and leishmaniasis is to develop novel inhibitors of the parasite-
specific enzyme trypanothione reductase. A lead inhibitor based on a 
peptoid structure was designed in the present study based on the known 
strong competitive inhibition of trypanothione reductase by N-benzoyl-
Leu-Arg-Arg-beta-naphthylamide and N-benzyloxycarbonyl-Ala-Arg-Arg-4-
methoxy- beta-naphthylamide. In the target peptoid the arginyl residues 
were replaced by alkylimidazolium units and the benzyloxycarbonyl group 
by the benzylaminocarbonyl function. The peptoid was synthesised using t
-butoxycarbonyl protection chemistry and couplings were activated by 2-(
1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. 
The resulting peptoid was shown to be a competitive inhibitor of 
recombinant trypanothione reductase from Trypanosoma cruzi with a K(i) 
value of 179 microM and with only weak inhibition of human erythrocyte 
glutathione reductase (the inhibition of glutathione reductase was at 
least 291-fold weaker than of trypanothione reductase).

REQUEST: [ sand fly ]

(0 articles match this request)

REQUEST: [ sandfly ]

(0 articles match this request)

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