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71.
Richard A. Urbanowicz Krzysztof Lacek Armin Lahm Krystyna Bienkowska‐Szewczyk Jonathan K. Ball Alfredo Nicosia Riccardo Cortese Antonello Pessi 《Journal of peptide science》2015,21(9):743-749
Immunoadhesins are engineered proteins combining the constant domain (Fc) of an antibody with a ligand‐binding (adhesion) domain. They have significant potential as therapeutic agents, because they maintain the favourable pharmacokinetics of antibodies with an expanded repertoire of ligand‐binding domains: proteins, peptides, or small molecules. We have recently reported that the addition of a cholesterol group to two HIV antibodies can dramatically improve their antiviral potency. Cholesterol, which can be conjugated at various positions in the antibody, including the constant (Fc) domain, endows the conjugate with affinity for the membrane lipid rafts, thus increasing its concentration at the site where viral entry occurs. Here, we extend this strategy to an HIV immunoadhesin, combining a cholesterol‐conjugated Fc domain with the peptide fusion inhibitor C41. The immunoadhesin C41‐Fc‐chol displayed high affinity for Human Embryonic Kidney (HEK) 293 cells, and when tested on a panel of HIV‐1 strains, it was considerably more potent than the unconjugated C41‐Fc construct. Potentiation of antiviral activity was comparable to what was previously observed for the cholesterol‐conjugated HIV antibodies. Given the key role of cholesterol in lipid raft formation and viral fusion, we expect that the same strategy should be broadly applicable to enveloped viruses, for many of which it is already known the sequence of a peptide fusion inhibitor similar to C41. Moreover, the sequence of heptad repeat‐derived fusion inhibitors can often be predicted from genomic information alone, opening a path to immunoadhesins against emerging viruses. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
72.
Annexin A1 (ANXA1, lipocortin-1) is the first characterized member of the annexin superfamily of proteins, so called since their main property is to bind (i.e., to annex) to cellular membranes in a Ca(2+) -dependent manner. ANXA1 has been involved in a broad range of molecular and cellular processes, including anti-inflammatory signalling, kinase activities in signal transduction, maintenance of cytoskeleton and extracellular matrix integrity, tissue growth, apoptosis, and differentiation. New insights show that endogenous ANXA1 positively modulates myoblast cell differentiation by promoting migration of satellite cells and, consequently, skeletal muscle differentiation. This suggests that ANXA1 may contribute to the regeneration of skeletal muscle tissue and may have therapeutic implications with respect to the development of ANXA1 mimetics. 相似文献
73.
Upadhyay AK Rotili D Han JW Hu R Chang Y Labella D Zhang X Yoon YS Mai A Cheng X 《Journal of molecular biology》2012,416(3):319-327
BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases. 相似文献
74.
Pilla P Sandomenico A Malachovská V Borriello A Giordano M Cutolo A Ruvo M Cusano A 《Biosensors & bioelectronics》2012,31(1):486-491
We present a fast and effective method for anchoring bioreceptors to optical waveguides exhibiting a poorly reactive polymer interface and that have to be minimally perturbed with respect to their design. The study originated from the need to biofunctionalize a fiber optic Long Period Grating (LPG) that is tuned in a highly sensitive working point, the so-called transition mode, through the deposition of a high refractive index overlay. In particular, a thin film of atactic polystyrene (PS) was dip-coated onto the LPG with a thickness suitable to optimize the LPG sensitivity to refractive index changes of the surrounding medium. Bovine serum albumin was selected as sacrificial layer for its well-known adhesion capabilities to PS surfaces, then glutaraldehyde was used to conjugate IgGs, serving as prototypical bioreceptor, on the device surface. The effectiveness of the immobilization method was assessed by studying the interaction between the immobilized IgG with a suitable anti-IgG. In a preliminary study performed by means of ELISA and surface plasmon resonance, optimal conditions for the biomolecular testing with the LPG were assessed. Four distinct interactions were thus monitored in real time following the shift of the LPG attenuation band. These experiments suggest a novel and interesting biofunctionalization approach of unreactive polymers with applications in immunosensing and basic life science research. 相似文献
75.
Merlino A Russo Krauss I Rossi B Vergara A De Vendittis A Marco S De Vendittis E Sica F 《Biochimie》2012,94(3):768-775
Superoxide dismutases are enzymes that protect biological systems against oxidative damage caused by superoxide radicals. In this paper, a detailed characterization is presented on the stability of SmSOD, the dimeric cambialistic superoxide dismutase from the dental pathogenic microorganism Streptococcus mutans, towards temperature and guanidine hydrochloride. Thermal and chemical denaturations were investigated by means of circular dichroism, fourth-derivative UV spectroscopy and fluorescence measurements. Data indicate that SmSOD is endowed with a significant thermostability and that both its thermal and guanidine hydrochloride-induced unfolding processes occur through a three-state model, characterized by a catalytically active dimeric intermediate species. To our knowledge, SmSOD is the smallest known dimeric protein that populates a well-structured active dimeric rather than a monomeric intermediate during unfolding processes. 相似文献
76.
Balsamo A Sannino F Merlino A Parrilli E Tutino ML Mazzarella L Vergara A 《Biochimie》2012,94(4):953-960
All tetrameric hemoglobins from Antarctic fish, including that from Trematomus bernacchii, HbTb form in the ferric state, promptly and distinctively from all the other tetrameric hemoglobins, a mixture of aquo-met at the α subunits and bis-histidyl adduct (hemichrome) at the β subunits. The role of the tertiary and quaternary structure in the hemichrome formation is unknown. Here we report the cloning, expression, purification, spectroscopic and computational characterization of the β-chain of HbTb (β-HbTb). Similarly to the human β-chains, β-HbTb self-assembles to form the homotetramer β(4)-HbTb; however, the latter quantitatively forms reversible ferric and ferrous bis-histidyl adducts, which are only partially present in the human tetramer (β(4)-HbA). A molecular dynamics study of the isolated β subunit of the two Hbs indicates that the ability to form hemichrome is an intrinsic feature of the chain; moreover, the greater propensity of β-HbTb to form the bis-histidyl adduct is probably linked to the higher flexibility of the CD loop region. On the bases of these experimental and computational results on the isolated chain, the influence of the quaternary structure on the stability of the endogenous ferrous and ferric hexa-coordination is also discussed. 相似文献
77.
Potenza N Salvatore V Migliozzi A Martone V Nobile V Russo A 《Nucleic acids research》2006,34(10):2906-2913
Human ribonuclease-1 (hRNase-1) is an extracellular enzyme found in exocrine pancreas, blood, milk, saliva, urine and seminal plasma, which has been implicated in digestion of dietary RNA and in antiviral host defense. The enzyme is characterized by a high catalytic activity toward both single-stranded and double-stranded RNA. In this study, we explored the possibility that hRNase-1 may also be provided with a ribonuclease H activity, i.e. be able to digest the RNA component of RNA:DNA hybrids. For this purpose, we developed an accurate and sensitive real-time RNase H assay based on a fluorogenic substrate made of a 12 nt 5′-fluorescein-labeled RNA hybridized to a complementary 3′-quencher-modified DNA. Under physiological-like conditions, hRNase-1 was found to cleave the RNA:DNA hybrid very efficiently, as expressed by a kcat/Km of 330 000 M−1 s−1, a value that is over 180-fold higher than that obtained with the homologous bovine RNase A and only 8-fold lower than that measured with Escherichia coli RNase H. The kinetic characterization of hRNase-1 showed that its hybridase activity is maximal at neutral pH, increases with lowering ionic strength and is fully inhibited by the cytosolic RNase inhibitor. Overall, the reported data widen our knowledge of the enzymatic properties of hRNase-1 and provide new elements for the comprehension of its biological function. 相似文献
78.
Cossu A Orrù S Jacomelli G Carcassi C Contu L Sestini S Corradi MR Pompucci G Carcassi A Micheli V 《Biochimica et biophysica acta》2006,1762(1):29-33
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency always causing hyperuricemia presents various degrees of neurological manifestations, the most severe which is Lesch-Nyhan syndrome. The HPRT gene is situated in the region Xq26-q27.2 and consists of 9 exons. At least 300 different mutations at different sites in the HPRT coding region from exon 1 to exon 9 have been identified. A new mutation in the HPRT gene has been determined in one patient with complete deficiency of erythrocyte activity, with hyperuricemia and gout but without Lesch-Nyhan disease. Analysis of cultured fibroblasts revealed minimal residual HPRT activity mainly when guanine was the substrate. Genomic DNA sequencing demonstrated patient's mother heterozygosity for the mutation and no mutation in her brother. The mutation consists in a C-->T transversion at cDNA base 463 (C463T) in exon 6, resulting in proline to serine substitution at codon 155 (P155S). This mutation had not been reported previously and has been designated HPRT(Sardinia). The mutation identified in this patient allows some expression of functional enzyme in nucleated cells such as fibroblasts, indicating that such cell type may add further information to conventional blood analysis. A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency. 相似文献
79.
Mai A Valente S Nebbioso A Simeoni S Ragno R Massa S Brosch G De Bellis F Manzo F Altucci L 《The international journal of biochemistry & cell biology》2009,41(1):235-247
Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us since 2001. Through structure-based drug design, two isomers of the APHA lead compound 1, the 3-(2-benzoyl-1-methyl-1H-pyrrol-4-yl)-N-hydroxy-2-propenamide 2 and the 3-(2-benzoyl-1-methyl-1H-pyrrol-5-yl)-N-hydroxy-2-propenamide 3 (iso-APHAs) were designed, synthesized and tested in murine leukemia cells as antiproliferative and cytodifferentiating agents. To improve their HDAC activity and selectivity, chemical modifications at the benzoyl moieties were investigated and evaluated using three maize histone deacetylases: HD2, HD1-B (class I human HDAC homologue), and HD1-A (class II human HDAC homologue). Docking experiments on HD1-A and HD1-B homology models revealed that the different compounds selectivity profiles could be addressed to different binding modes as observed for the reference compound SAHA. Smaller hydrophobic cap groups improved class II HDAC selectivity through the interaction with HD1-A Asn89-Ser90-Ile91, while bulkier aromatic substituents increased class I HDAC selectivity. Taking into account the whole enzyme data and the functional test results, the described iso-APHAs showed a behaviour of class I/IIb HDACi, with 4b and 4i preferentially inhibiting class IIb and class I HDACs, respectively. When tested in the human leukaemia U937 cell line, 4i showed altered cell cycle (S phase arrest), joined to high (51%) apoptosis induction and significant (21%) differentiation activity. 相似文献
80.
Donati C Hiller NL Tettelin H Muzzi A Croucher NJ Angiuoli SV Oggioni M Dunning Hotopp JC Hu FZ Riley DR Covacci A Mitchell TJ Bentley SD Kilian M Ehrlich GD Rappuoli R Moxon ER Masignani V 《Genome biology》2010,11(10):R107-19