Saturday, July 18, 2009

What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2009 Jul 18
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -7 of 7

1: Parasitol Res. 2009 Jul 16. [Epub ahead of print]Click here to read

The trypanocidal effect of NO-releasing agents is not due to inhibition of the major cysteine proteinase in Trypanosoma brucei.

Steverding D, Wang X, Sexton DW.

BioMedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK, dsteverding@hotmail.com.

The lysosomal cysteine proteinase activity of bloodstream forms of Trypanosoma brucei is a validated drug target. Previously, it was reported that nitric oxide (NO)-releasing agents inhibit the catalytic activity of cysteine proteinases of the protozoan parasites Leishmania infantum, Trypanosoma cruzi and Plasmodium falciparum. In this study, we investigated the effect of the NO-donors S-nitrosoglutathione, (+/-)-(E)-4-ethyl-2[(E)-hydroxyimino]-5-nitro-3-hexenamide, 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetyl-DL: -penicillamine on the activity of the cysteine proteinase of T. brucei. At a concentration of 1 mM, the NO donors inhibited the catalytic activity of purified T. brucei cysteine proteinase by 50-90%. With the exception of SIN-1, all NO donors displayed trypanocidal activities against bloodstream forms of T. brucei in vitro with 50% growth inhibition values of around 30 muM. However, the NO donors were ineffective in significantly inhibiting the cysteine proteinase activity within the parasites. This finding was confirmed by the ineffectiveness of the NO donors to block proteinolysis in the lysosome of the parasites. The results show that the trypanocidal activity of NO donors cannot be attributed to the inhibition of the major lysosomal cysteine proteinase in bloodstream forms of T. brucei.

PMID: 19609563 [PubMed - as supplied by publisher]

2: Protein Expr Purif. 2009 Jul 13. [Epub ahead of print]Click here to read

The production of recombinant human laminin-332 in a Leishmania tarentolae expression system.

Phan HP, Sugino M, Niimi T.

Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan.

Laminin (LM)-332 (alpha3beta3gamma2), a large heterotrimeric glycoprotein, is an essential component of epithelial basement membranes that promotes cell adhesion and migration. Here, we expressed human LM-332 using a novel protein expression system based on the trypanosomatid protozoan host Leishmania tarentolae. Plasmids containing cDNA encoding full-length beta3 and gamma2 subunits and truncated alpha3 subunit were sequentially introduced into L. tarentolae. A recombinant strain harboring the three subunits of human LM-332 efficiently formed heterotrimer and secreted it into the culture medium. Heterotrimeric recombinant LM-332 (rLM-332) could be purified from culture medium with one-step immuno-affinity chromatography. The eluted fraction contained all three subunits, as confirmed by immunoprecipitation and immunoblotting. The purified rLM-332 showed similar cell adhesion activity to rLM-332 purified from mammalian cells, indicating its proper folding and assembly. The obtained expression level was not high; however, we suggest that this expression system has the potential for mass-production of LMs for tissue engineering.

PMID: 19607924 [PubMed - as supplied by publisher]

3: J Med Chem. 2009 Jul 17. [Epub ahead of print]Click here to read

Synthesis and Antiprotozoal Activity of Pyridyl Analogues of Pentamidine.

Bakunova SM, Bakunov SA, Wenzler T, Barszcz T, Werbovetz KA, Brun R, Tidwell RR.

Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-7525.

A series of novel pyridyl analogues 1-18 of antiprotozoal drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) has been synthesized and tested for in vitro activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Antiprotozoal properties of compounds 1-18 depended on the placement of cationic moieties on the pyridine rings as well as the nature of substituents on the amidine groups. Diamidine 6 with cationic moieties adjacent to pyridine nitrogen atoms was the most promising compound in the series showing superior in vitro activities against T. brucei rhodesiense, P. falciparum, and L. donovani compared to pentamidine. An oral prodrug of diamidine 6, diamidoxime 9, administered at 25 mg/kg daily for 4 days, exhibited excellent antitrypanosomal efficacy in vivo curing all infected animals in the STIB900 acute mouse model of trypanosomiasis.

PMID: 19606902 [PubMed - as supplied by publisher]

4: J Med Chem. 2009 Jul 16. [Epub ahead of print]Click here to read

Neglected Tropical Diseases: Multi-Target-Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania.

Cavalli A, Bolognesi ML.

Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

PMID: 19606868 [PubMed - as supplied by publisher]

5: Lancet. 2009 Jul 4;374(9683):7-9. Epub 2009 Jun 24.Click here to read LinkOut
Comment on:
Lancet. 2009 Jul 4;374(9683):56-64.

NECT trial: more than a small victory over sleeping sickness.

Opigo J, Woodrow C.

District Health Services, Moyo District Local Government, Moyo, Uganda.

PMID: 19559477 [PubMed - indexed for MEDLINE]

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6: Bioorg Med Chem Lett. 2009 Jun 1;19(11):3031-5. Epub 2009 Apr 20.Click here to read LinkOut

Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase.

Cavalli A, Lizzi F, Bongarzone S, Brun R, Luise Krauth-Siegel R, Bolognesi ML.

Department of Pharmaceutical Sciences, Alma Mater Studiorum-Bologna University, Bologna, Italy.

Novel quinazoline-type compounds were designed as inhibitors of the parasite specific enzyme trypanothione reductase (TR), and their biological activities were evaluated. Some of our compounds inhibited TR, showed selectivity for TR over human glutathione reductase, and inhibited parasite growth in vitro. We propose that the quinazoline framework is a privileged structure that can be purposely modified to design novel TR inhibitors. Furthermore, the use of privileged motifs might emerge as an innovative approach to antiparasitic lead candidates.

PMID: 19414258 [PubMed - indexed for MEDLINE]

7: Proteins. 2009 Jul;76(1):138-50.Click here to read LinkOut

Inclusion of ionization states of ligands in affinity calculations.

Donnini S, Villa A, Groenhof G, Mark AE, Wierenga RK, Juffer AH.

The Biocenter Oulu and the Department of Biochemistry, University of Oulu, Oulu, Finland.

When estimating binding affinities of a ligand, which can exists in multiple forms, for a target molecule, one must consider all possible competing equilibria. Here, a method is presented that estimates the contribution of the protonation equilibria of a ligand in solution to the measured or calculated binding affinity. The method yields a correction to binding constants that are based on the total concentration of inhibitor (the sum of all ionized forms of the inhibitor in solution) to account for the complexed form of the inhibitor only. The method is applied to the calculation of the difference in binding affinity of two inhibitors, 2-phosphoglycolate (PGA) and its phoshonate analog 3-phosphonopropionate (3PP), for the glycolytic enzyme triosephosphate isomerase. Both inhibitors have three titrating sites and exist in solution as a mixture of different forms. In this case the form that actually binds to the enzyme is present at relative low concentrations. The contributions of the alternative forms to the difference in binding energies is estimated by means of molecular dynamics simulations and corrections. The inhibitors undergo a pK(a) shift upon binding that is estimated by ab initio calculations. An interesting finding is that the affinity difference of the two inhibitors is not due to different interactions in the active site of the enzyme, but rather due to the difference in the solvation properties of the inhibitors.

PMID: 19089986 [PubMed - indexed for MEDLINE]

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