RESUMEN
Glycodendrimers bearing Tn (alpha-D-GalNAc-(1 --> O)-Ser/Thr), an identified tumor-associated carbohydrate antigen, hold promise in the post-surgery treatment of a variety of tumors such as metastatic breast cancer. We used molecular dynamics (MD) techniques to examine structural differences taking place during synthesis of two classes of tetravalent Multiple Antigen Glycopeptides (MAG) that differ only by the gamma-Abu insert in the structure of the oligolysine core. Each of the selected intermediates of the synthesis was modeled, subjected to the 2 ns run in N,N'-dimethylformamide (DMF) and geometrically characterized. We characterized: a) distances of free, or extended termini from the anchor, b) interatomic distances between free or substituted N termini, c) radius of gyration and d) spatial distribution of molecular density. A detailed conformational analysis of 16 glycodendrimers shows the distinct behavior of the inserted vs. non-inserted constructs already during the first steps of the modeled synthesis. It suggests that the character as well as the length of the insert has a major impact on the spatial characteristics and behavior of the dendritic molecules. The inserts can, in principle, increase a tendency of dendrimers to establish a high-density core, which is similar to the effect of a higher generation.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/química , Dimetilformamida/química , Glicopéptidos/química , Polilisina/química , Ácido gamma-Aminobutírico/química , Reactivos de Enlaces Cruzados/química , Modelos Moleculares , Polímeros/química , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Neutrophils contain several cationic antimicrobial proteins or peptides (CAPs) that exert antibiotic-like action against bacteria. These host-derived antibiotics kill susceptible bacteria by oxygen-independent mechanisms. Considerable interest in their activity has been generated in recent years due not only to their likely important role in innate host defense against infection, but also their possible use as therapeutic agents in treating infections caused by antibiotic-resistant pathogens. We have studied the antibacterial properties of human lysosomal cathepsin G (cat G). This highly cationic serine protease contains at least three antibacterial regions that by themselves can exert antibacterial action against Gram-negative bacteria, such as Pseudomonas aeruginosa. Only one of these peptides, defined by residues 117-136 of full-length cat G, has bactericidal action against Gram-positive pathogens, such as Staphylococcus aureus. Due to the broad-spectrum antibacterial action of this peptide, we have sought to define the amino acids within its primary sequence required for this activity and have developed variants with improved activity. This review emphasizes the importance of both cationicity and hydrophobicity as necessary characteristics for the antibacterial action of CAPs. It also proposes the strategy that naturally occurring large human CAPs can be dissected to smaller CAPs and then modified to enhance their activity in vitro. This approach could prove beneficial to those interested in developing antimicrobial peptides as therapeutic agents.
Asunto(s)
Antibacterianos/química , Catepsinas/química , Farmacorresistencia Bacteriana , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Antibacterianos/farmacología , Catepsina G , Catepsinas/farmacología , Diseño de Fármacos , Humanos , Lisosomas/química , Lisosomas/enzimología , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Neutrófilos/química , Neutrófilos/enzimología , Neutrófilos/ultraestructura , Serina Endopeptidasas , Staphylococcus aureus/efectos de los fármacosRESUMEN
Recent progress in peptide and glycopeptide chemistry make the preparation of peptide and glycopeptide dendrimers of acceptable purity, with designed structural and immunochemical properties reliable. New methodologies using unprotected peptide building blocks have been developed to further increase the possibilities of their design and improve their preparation and separation. The sophisticated design of peptide and glycopeptide dendrimers has led to their use as antigens and immunogens, for serodiagnosis and other biochemical uses including drug delivery. Dendrimers bearing peptide with predetermined secondary structures are useful tools in protein de novo design. This article covers synthesis and applications of multiple antigen peptides (MAPs), multiple antigen glycopeptides (MAGs), multiple antigen peptides based on sequential oligopeptide carriers (MAP-SOCs), glycodendrimers and template-assembled synthetic proteins (TASPs). In part II the preparation of MAPs, and the utility of glycodendrimers and TASPs are discussed.
Asunto(s)
Glicopéptidos/química , Péptidos/química , Secuencia de Aminoácidos , BiopolímerosRESUMEN
Isoproterenol (2 mg/kg) injected subcutaneously into male Sprague-Dawley rats elicited morphological damage in the endomyocardium which was analyzed 16 h following injection. Our aim was to study the relationship between damaged individual myocytes and their capillary supply. Myocardial tissue sections were differentially stained in order to distinguish arteriolar (AC) and venular (VC) capillary portions. Tissue areas surrounding individual capillaries and the position of the capillaries with respect to the damaged individual myocytes were established by using the method of "capillary domains". In multicellular necrotic lesions 84% of the capillaries located within the necrotic foci and 77% of the capillaries in the surrounding tissue area were identified as the distal, venular portion with presumably low O2 content. The proportion of VCs related to necrotic lesions was significantly higher than in surviving endomyocardial regions. In the case of individual necrotic myocytes, we found 88% to be supplied by VCs, while the adjacent normal myocytes were supplied by 61% VCs. Both values were significantly higher when compared to control hearts (42%). These results strongly support the crucial role of a lack of oxygen delivery in the pathogenesis of isoproterenol-induced necrosis.