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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aerosol solvent extraction system (ASES) is a method based on solvent extraction using supercritical carbon dioxide for the preparation of microspheres. The ASES technology seems to be strongly affected by physico-chemical properties of biodegradable polymers, leading to incomplete or unsuccessful microsphere formation. The number of suitable polymers for ASES, such as poly(L-lactide) (L-PLA) and poly(beta-hydroxy-butyric acid) (PHB) is rather limited for unknown reasons. Therefore linear and novel branched polyesters were synthesized and subjected to the ASES process to explore the function property relationship. The properties of these polymers as well as of the ASES products were characterized by NMR spectroscopy, differential scanning calorimetry, light scattering, wide-angle X-ray scattering and scanning electron microscopy. It appears that high degrees of polymer crystallinity are the key factor for successful microsphere formation using the ASES process. Under the conditions investigated two types of polymers were especially suitable: semi-crystalline comb polyesters as well as comb polyesters in which crystallinity could be induced. These novel polymers are of particular interest for the ASES encapsulation technology since they combine beneficial properties both controlling drug release due to their three-dimensional architecture and faster biodegradability with sufficient mechanical stability to allow particle formation using supercritical carbon dioxide.
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PMID:Biodegradable semi-crystalline comb polyesters influence the microsphere production by means of a supercritical fluid extraction technique (ASES). 1064 May 80

Four new bioactive pyridinium alkaloids, named spongidines A-D (5-8), have been isolated from a Vanuatu sponge of the genus Spongia, together with known petrosaspongiolides D (1) and G (2). Compounds 3 and 4 are 21-hydroxy derivatives of petrosaspongiolides K and P. Structure elucidation was accomplished through extensive 2D NMR experiments (COSY, ROESY, HMBC, HMQC) and IR, UV, and FABMS data. All compounds significantly inhibited human synovial phospholipase A(2) (PLA(2)) at 10 microM, with an IC(50) value of 5.8 microM for compound 4, which is the most potent inhibitor, with a higher selectivity toward this enzyme than the reference inhibitor manoalide. Pyridinium alkaloids (5-8) mainly inhibited human synovial PLA(2). Compound 8, which contains a sulfonic acid group, is the most interesting inhibitor.
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PMID:New pyridinium alkaloids from a marine sponge of the genus Spongia with a human phospholipase A(2) inhibitor profile. 1075 11

To obtain biodegradable polymers with variable surface properties for tissue culture applications, poly(ethylene glycol) blocks were attached to poly(lactic acid) blocks in a variety of combinations. The resulting poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether (Me.PEG-PLA) diblock copolymers were subject to comprehensive investigations concerning their bulk microstructure and surface properties to evaluate their suitability for drug delivery applications as well as for the manufacture of scaffolds in tissue engineering. Results obtained from 1H-NMR, gel permeation chromatography, wide angle X-ray diffraction and modulated differential scanning calorimetry revealed that the polymer bulk microstructure contains poly(ethylene glycol)-monomethyl ether (Me.PEG) domains segregated from poly(D,L-lactic acid) (PLA) domains varying with the composition of the diblock copolymers. Analysis of the surface of polymer films with atomic force microscopy and X-ray photoelectron spectroscopy indicated that there is a variable amount of Me.PEG chains present on the polymer surface, depending on the polymer composition. It could be shown that the presence of Me.PEG chains in the polymer surface had a suppressive effect on the adsorption of two model peptides (salmon calcitonin and human atrial natriuretic peptide). The possibility to modify polymer bulk microstructure as well as surface properties by variation of the copolymer composition is a prerequisite for their efficient use in the fields of drug delivery and tissue engineering.
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PMID:Biodegradable poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether diblock copolymers: structures and surface properties relevant to their use as biomaterials. 1105 83

There is abundant evidence that the plasminogen activator (PA) system with its key components uPA (urokinase-type plasminogen activator), its cell surface receptor uPA-R (CD87) and its inhibitor PAI-1 plays a key role in tumour invasion and metastasis. Elevated levels of these factors in tumour tissue are associated with tumour aggressiveness and poor patient outcome. Animal models suggest that the PA system is not essential for fertility or survival under physiological conditions. Thus, it seems well suited as a therapeutic target for patients with solid malignant tumours. Novel therapy concepts targeting the uPA system are currently being explored. A variety of different synthetic uPA inhibitor classes have been developed over the last decades. First generation inhibitors displayed a low uPA inhibitory potency combined with broad specificity. More recently, structure based design, x-ray crystallographic screening or NMR based screening have revealed a large number of new, potent and selective uPA-inhibitors. A few modern compounds have shown promising results in preclinical testing and are now ready for Phase I clinical studies. Other therapeutic strategies such as antagonists of uPA/uPA-R interaction or gene therapeutic approaches to suppress the uPA-system are still being evaluated in in vitro and in vivo models. For clinical application, a combination therapy targeting more than one of the interacting proteolytic pathways may be required for effective antiproteolytic therapy. In addition, antiproteolytic agents may provide additive or synergistic treatment benefits if used in combination together with conventional therapeutics, in particular in those solid tumours for which potent conventional regimens already exist.
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PMID:Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. 1172 4

Poly(lactic acid)-poly(ethylene glycol)-biotin (PLA-PEG-biotin) is a degradable polymer with protein resistant properties that can undergo rapid surface engineering in aqueous media to create biomimetic surfaces. Surface engineering of this polymer is dependent on biomolecular interactions between the biotin end group and the protein avidin. Given the vigorous conditions of synthesis, it is essential that the manufacture of the polymer does not alter the biotin structure or its molecular recognition. Equally, it is important that the incorporation of biotin does not adversely affect the physicochemical properties of the polymer. (1)H NMR provides evidence of biotin attachment and structural integrity. (1)H NMR, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC) analysis shows there is no significant effect on bulk properties induced by the biotin end group. Surface plasmon resonance (SPR) and fluorescent spectroscopy studies using the 2-(4'-hydroxyazobenzene) benzoic acid (HABA)/avidin complex show that the biotin moieties binding capabilities are not impaired by the synthesis.
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PMID:Synthesis and characterisation of a degradable poly(lactic acid)-poly(ethylene glycol) copolymer with biotinylated end groups. 1174 23

A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses. Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared. Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions. Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC. SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37 degrees C for up to 5 weeks. NMR showed a decrease in the CH2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded. In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for approximately 2 months in a static system. It was observed that release was according to Higuchi kinetics (Q vs. t(1/2)), and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.
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PMID:Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks. 1181 62

In this study, the x-ray crystal structures of the calcium-free and calcium-bound forms of phospholipase A(2) (PLA(2)), produced extracellularly by Streptomyces violaceoruber, were determined by using the multiple isomorphous replacement and molecular replacement methods, respectively. The former and latter structures were refined to an R-factor of 18.8% at a 1.4-A resolution and an R-factor of 15.0% at a 1.6-A resolution, respectively. The overall structure of the prokaryotic PLA(2) exhibits a novel folding topology that demonstrates that it is completely distinct from those of eukaryotic PLA(2)s, which have been already determined by x-ray and NMR analyses. Furthermore, the coordination geometry of the calcium(II) ion apparently deviated from that of eukaryotic PLA(2)s. Regardless of the evolutionary divergence, the catalytic mechanism including the calcium(II) ion on secreted PLA(2) seems to be conserved between prokaryotic and eukaryotic cells. Demonstrating that the overall structure determined by x-ray analysis is almost the same as that determined by NMR analysis is useful to discuss the catalytic mechanism at the molecular level of the bacterial PLA(2).
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PMID:The crystal structure of prokaryotic phospholipase A2. 1189 85

Until now, phospholipase A(2) (PLA(2); EC 3.1.14) has been found only from eukaryotic sources. In the present study, we found a secreted PLA(2), which is produced by a soil bacterium, Streptomyces violaceoruber A-2688, demonstrating that the enzyme is the first phospholipase A(2) identified in prokaryote. After characterization of the novel PLA(2), a gene encoding the enzyme was cloned, sequenced, and overexpressed using a Streptomyces host-vector system. The amino acid sequence showed that the prokaryotic PLA(2) has only four cysteines and less homology to the eukaryotic ones, which have 12-16 cysteines. The solution structures of the prokaryotic PLA(2), bound and unbound with calcium(II) ion, were determined by using the NMR technique and structure calculation. The overall structure of the S. violaceoruber PLA(2), which is composed of only five alpha-helices, is completely different from those of eukaryotic PLA(2)s, which consist of beta-sheets and alpha-helices. The structure of the calcium-binding domain is obviously distinct from that without the ion; the ligands for the calcium(II) ion are the two carboxylates of Asp(43) (monodentate) and Asp(65) (bidentate), the carbonyl oxygen of Leu(44), and three water molecules. A calcium-binding experiment showed that the calcium dissociation constant ( approximately 5 mm) for the prokaryotic PLA(2) is much larger than those of eukaryotic ones.
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PMID:A novel prokaryotic phospholipase A2. Characterization, gene cloning, and solution structure. 1189 86

13C cross-polarization/magic angle spinning (CP/MAS) NMR and (1)H T(1rho) experiments of poly(L-alanine) (PLA), poly(L-valine) (PLV), and PLA/PLV blends have been carried out in order to elucidate the conformational stability of the polypeptides in the solid state. These were prepared by adding a trifluoroacetic acid (TFA) solution of the polymer with a 2.0 wt/wt % of sulfuric acid (H(2)SO(4)) to alkaline water. From these experimental results, it is clarified that the conformations of PLA and PLV in their blends are strongly influenced by intermolecular hydrogen-bonding interactions that cause their miscibility at the molecular level.
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PMID:A study of conformational stability of poly(L-alanine), poly(L-valine), and poly(L-alanine)/poly(L-valine) blends in the solid state by (13)C cross-polarization/magic angle spinning NMR. 1194 39

The preparation and characterization of a series of closely related magnesium and zinc compounds are reported: LMg(N(i)Pr(2))(THF), 1; LZn(N(i)Pr(2)), 2; LMg(O(t)Bu)(THF), 3; LZn(O(t)Bu), 4; and LZn(OSiPh(3))(THF), 6; where L = CH(CMeNC(6)H(3)-2,6-(i)Pr(2))(2). Their dynamic solution behavior has been examined by variable-temperature NMR studies and reveals that THF reversibly dissociates in toluene-d(8) or CD(2)Cl(2) and that exchange with free THF occurs by a dissociative process. Compounds 1-4 and 6 all initiate and subsequently sustain ring-opening polymerization (ROP) of lactides. For a related series of compounds LMX(THF)(n)(), where n = 1 or 0, the rate of initial ring-opening follows the order M = Mg > Zn and X = O(t)Bu > N(i)Pr(2) > NSi(2)Me(6) > OSiPh(3). In THF at 25 degrees C, compounds 3 and 4 polymerize 100 equiv of rac-lactide to >95% conversion in 5 and 80 min for M = Mg and Zn, respectively, and yield ca. 90% heterotactic PLA, (isi + sis tetrads). The reactions proceed faster in methylene chloride, but for M = Mg, a Bernoulian distribution of tetrads is formed from rac-lactide (3iii:2isi:sii:sis:iis) prior to trans-esterification. Polymerization of L-LA in toluene-d(8) and THF-d(8) by 3 and 4 have been studied by VT (1)H NMR spectroscopy: the resting state for zinc is proposed to be a monomeric species akin to LZn(eta(2)-OCHMeC(O)OMe), whereas the magnesium complex appears to be dimeric LMg(mu-OP)(2)MgL. None of the compounds is capable of initiating homopolymerization of propylene oxide (PO) or cyclohexene oxide (CHO), although the magnesium amide 1 effects ring-opening by allylic proton abstraction and the dimeric compound [LMg(mu-OC(6)H(9))](2), 7, is formed. Reactions with carbon dioxide are also described, along with the characterization of LZnO(2)CN(i)Pr(2), 8, which is shown to be inert with respect to CHO and PO at room temperature. All the compounds are hydrolytically sensitive, and LZn(mu-OH)(2)ZnL, 5, has been isolated from hydrolysis of compound 4. The crystal and molecular structures are reported for compounds 1-5, 7, and 8. These results are compared with those recently reported by Coates et al.
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PMID:Coordination chemistry and reactivity of monomeric alkoxides and amides of magnesium and zinc supported by the diiminato ligand CH(CMeNC(6)H(3)-2,6-(i)Pr(2))(2). A comparative study. 1200 4


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