Biomedical subjects

M Paulino

Publications and source records attributed to M Paulino.

8 recordsLinked to original sources

PubMed2005

The chemotherapy of chagas' disease: an overview.

The review presents: a) a brief description of the disease; b) a summary of the most important metabolic targets so far identified in Trypanosome cruzi (T. cruzi) along with corresponding inhibitor compounds; c) the current state of knowledge on the trypanothione reductase system of trypanosomatids with reference to oxidative stress defenses; d) detailed discussions on T. cruzi trypanothione reductase inhibitors such as nitrofuranes, naphthoquinones and phenothiazines. As yet, the chemotherapy of Chagas' disease remains an unsolved problem. Further search for new drugs must continue by means of nucleating existing chemotherapy efforts.

Animals↗

PubMed2000

Molecular cloning, sequencing and expression of a serine proteinase inhibitor gene from Toxoplasma gondii.

A cDNA clone from a Toxoplasma gondii tachyzoite cDNA library encoding a serine proteinase inhibitor (serpin) was isolated. The 1376 bp cDNA sequence encodes a 294 amino acid protein with a putative signal peptide of 23 amino acids resulting in a mature protein with a predicted mass of 30,190 Da and a pI of 4.86. This protein has internal sequence similarity of residues 30-66, 114-150, 181-217 and 247-283 indicating a four-domain structure. The four domains exhibit high identity to serine proteinase inhibitors belonging to the non-classical Kazal-type family. The gene is single copy in the tachyzoite haploid genome of RH strain and was amplified by polymerase chain reaction (PCR). Several introns were identified. The sequence encoding the mature protein was amplified by PCR, cloned into the pQE30 vector and expressed in Escherichia coli. Specific antiserum generated against the recombinant protein was used in immunoblot assay and two bands of 38 and 42 kDa were detected in a whole parasite homogenate. The recombinant protein showed trypsin-inhibitory activity, one of the two potential specificities. We discuss the possible roles that T. gondii serpin(s) may play in the survival of the tachyzoites in the host.

Amino Acid Sequence↗

PubMed2000

Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure-activity relationships.

Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.

Aldehydes↗

PubMed1998

Synthesis and anti-trypanosomal activity of novel 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives.

Several novel semicarbazones derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde, and tested in vitro as potential anti-trypanosomal agents. The compounds were prepared in good to excellent yields in 2-3 steps from readily available starting materials. Some derivatives were found to be active against Trypanosoma cruzi with an activity similar to that of Nifurtimox.

Animals↗

PubMed1998

Modelling a 3D structure for EgDf1 from Echinococcus granulosus: putative epitopes, phosphorylation motifs and ligand.

EgDf1 is a developmentally regulated protein from the parasite Echinococcus granulosus related to a family of hydrophobic ligand binding proteins. This protein could play a crucial role during the parasite life cycle development since this organism is unable to synthetize most of their own lipids de novo. Furthermore, it has been shown that two related protein from other parasitic platyhelminths (Fh15 from Fasciola hepatica and Sm14 from Schistosoma mansoni) are able to confer protective inmunity against experimental infection in animal models. A three-dimensional structure would help establishing structure/function relationships on a knowledge based manner. 3D structures for EgDf1 protein were modelled by using myelin P2 (mP2) and intestine fatty acid binding protein (I-FABP) as templates. Molecular dynamics techniques were used to validate the models. Template mP2 yielded the best 3D structure for EgDf1. Palmitic and oleic acids were docked inside EgDf1. The present theoretical results suggest definite location in the secondary structure of the epitopic regions, consensus phosphorylation motifs and oleic acid as a good ligand candidate to EgDf1. This protein might well be involved in the process of supplying hydrophobic metabolites for membrane biosynthesis and for signaling pathways.

Amino Acid Sequence↗

PubMed1998

DNA structure and fluctuations sensed from a 1.1ns molecular dynamics trajectory of a fully charged Zif268-DNA complex in water.

Molecular dynamics simulations of the zinc finger domain of protein Zif268, in a complex with a high affinity DNA sequence, yields a globally stable system with small yet significant readjustments with persistence time of the order of 1.1ns. The results confirm the quality of the standard GROMOS87 force field with a corrected solvent-to-solute interaction that does not affect the water-water SPC interactions nor the intra-molecular cohesive forces. Specificity determinants are discussed. The simulations of DNA alone, with the same force field, showed the important role played by the solvent and the symmetry of the counterion distribution. (Tapia & Velázquez, J. Am. Chem. Soc., 119, 5934, 1997) In the present work, this feature was retained when appropriate. The results for root mean square deviations and temperature B-factors illustrate the reliability of this approach. The structure of DNA is held by its interactions with the zinc finger protein. This behavior is not much affected by the slow whithering away of finger-1 from DNA. The factors contributing to the molecular stability found in GROMOS' potential energy function appear to be sufficient to yield stable fluctuation patterns when surrounding medium effects are properly included.

Computer Simulation↗

PubMed1997

Remarks on the phylogeny and structure of fatty acid binding proteins from parasitic platyhelminths.

Four fatty acid binding proteins (FABPs) have been described in 4 parasitic platyhelminths: Schistosoma mansoni, Schistosoma japonicum, Fasciola hepatica and Echinococcus granulosus. FABPs form a multigenic family of cytosolic proteins widely distributed in metazoan tissues, the function of which is still poorly understood. These helminth proteins have recently received attention, since there are reports to indicate that S. mansoni and F. hepatica FABPs may be protective antigens. In addition, these proteins could play a major role in the parasites' life-cycles because platyhelminths are unable to synthesize de novo most of their lipids. We have undertaken phylogenetic and structural analyses of platyhelminth FABPs in an attempt to characterize features of biological relevance. Phylogenetically, these FABPs appear to be more closely related to those of vertebrate heart, mammary gland, muscle, retina, skin, brain and myelin, although no clear functional relationships were established between them. We describe several conserved motifs characteristic of specific groups of FABPs. Hydrophilicity, flexibility and accessibility analyses revealed several major putative epitopes for the E. granulosus FABP, EgDf1, that appear to be centred in loops of the EgDf1 3-dimensional structure modelled by molecular replacement.

Amino Acid Sequence↗

PubMed1996

A new analogue of nifurtimox.

1-¿[(5-Nitro-2-furyl)methylene]amino¿-1,2,4-triazole, C7H5N5O3, is a new analogue of nifurtimox with activity against Tripanosoma cruzi. In the crystal structure, the molecule lies on a mirror plane and has an E-sZ conformation along the N = C-C moiety. The molecules are linked through C-H...O and C-H...N interactions.

Antiprotozoal Agents↗