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Biomedical subjects

A Tossi

Publications and source records attributed to A Tossi.

26 records · Page 2Linked to original sources
PubMed1994

Chemical synthesis and biological activity of a novel antibacterial peptide deduced from a pig myeloid cDNA.

Several myeloid precursors of antibacterial peptides have recently been shown to share homologous pre- and pro-regions. Taking advantage of this homology, a novel cDNA was cloned from pig bone marrow RNA. This encodes a 166-residue polypeptide with highly conserved pre- (29 residues) and pro- (101 residues) sequences, followed by a unique, 36-residue C-terminal sequence. Structure analyses of this C-terminal region have identified a highly cationic sequence predicted to adopt an amphipathic alpha-helical conformation. A peptide corresponding to this sequence was chemically synthesized and shown to arrest the growth of both Gram-positive and Gram-negative bacteria. At least for Escherichia coli, the activity of this peptide appears to be mediated by its ability to permeabilize the bacterial membranes.

Amino Acid Sequence↗
PubMed1994

Structural characterization of synthetic model peptides of the DNA-binding cI434 repressor by electrospray ionization and fast atom bombardment mass spectrometry.

The structural characterization of two synthetic model peptides of the cI434 repressor is described. Unequivocal determination of the structure was achieved by means of electrospray ionization mass spectrometry of the intact peptides and by fast atom bombardment mass spectrometric identification of complementary peptide fragments obtained by tryptic and chymotrypic digestion and partial separation by reversed-phase high-performance liquid chromatography. The results show the potential of this approach for characterizing synthetic peptides of relatively high molecular weight.

Amino Acid Sequence↗
PubMed1994

Substrate specificity of CDC2 kinase from human HeLa cells as determined with synthetic peptides and molecular modeling.

A systematic study was undertaken in order to assess the substrate specificity of cyclin-B/cell division control protein kinase (CDC2) isolated from human HeLa cells, using 13-15 residue peptides with a central histone-like KKSPKK motif as a model. Replacement of the proline residue by any of the other 19 amino acids or D-proline drastically reduces or abolishes phosphorylation by CDC2. Changing the basic residues to Ala on either side of the -SP- structure differentially reduces phosphorylation. Molecular modeling and dynamics simulation indicated that the phosphorylation site of the peptide may have to adopt a turn-like conformation that will orientate the charged and hydrophobic residues so as to allow interaction with postulated binding surfaces within the CDC2 active site. It thus appears that, of the 20 coded amino acids, only proline can provide this conformation in short peptides. This is in agreement with the finding that sarcosine can replace proline in this respect (S. Ando et al. Biochem. Biophys. Res. Commun. 195, 837-843, 1993).

Amino Acid Sequence↗
PubMed1992

Improved detection of homology in distantly related proteins: similarity of adducin with actin-binding proteins.

A novel and generally applicable method is described for the detection of homology in distantly related proteins using a new domain sequence database that contains over 20,000 protein sequence segments of known function. The use of the method is illustrated on distantly related domains shared by complement components C1S and C1R, calcium-dependent serine proteinase and bone morphogenetic protein 1. New homologies are shown between human adducin and the actin-binding domains of alfa-actinin and dystrophin.

Actinin↗
PubMedDate not supplied

Localization of beta-defensin genes in non human primates.

Defensins are a family of host defence peptides that play an important role in the innate immunity of mammalian and avian species. In humans, four beta-defensins have been isolated so far, corresponding to the products of the genes DEFB1 (h-BD1, GenBank accession number NM_005218); DEFB4 (h-Bd2, NM_004942.2), DEFB103 (h-BD3, NM_018661); and DEFB104 (hBD4, NM_080389) mapping on chromosome 8p23.22. We have localized beta-defensin genes on metaphasic chromosomes of great apes and several non-human primate species to determine their physical mapping. Using fluorescent in situ hybridization and BAC probes containing the four beta-defensin genes, we have mapped the homologous regions to the beta-defensin genes on chromosome 8p23-p.22 in non-human primates, while no signals were detected on prosimians chromosomes.

Animals↗
PubMedDate not supplied

Development of pseudopeptide inhibitors of HIV-1 aspartic protease: analysis and tuning of the subsite specificity.

HIV-1 aspartic protease (PR) is a promising target for acquired immunodeficiency syndrome (AIDS) therapy, and the development of PR inhibitors can be accelerated by computer-aided design methods. We describe an approach for the design of new inhibitors, based on the modification of a known reference inhibitor, and the calculation of relative binding energies, taking into account contributions from all species in the binding equilibrium (inhibitor, PR and inhibitor/PR complex), as well as their solvation. This allows for a rational selection of new structures that are likely to have increased inhibition potency. We have analyzed reduced amide bond hexapeptides (Ac-P3-P2-P1-phi[CH2-NH]-P1'-P2-P3'-NH2), based on the structure of the known inhibitor MVT-101. A maximum gain in binding energy (approximately -55 kcal/mol) is observed when Phe or Tyr are present in positions P1 and P1', Glu in position P2' and aromatic residues (Phe, Trp or Tyr) in positions P3 and P3', while, in general, the presence of positively charged residues is destabilizing. This specificity is explained in terms of the interaction of individual inhibitor residues with proximal and distal PR residues. The validity of this computational approach has been confirmed by solid-phase synthesis of several of the designed pseudopeptides, followed by in vitro enzyme inhibition assaying. The best candidate structures show IC50 values in the low nanomolar range.

Amino Acid Sequence↗