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September 2006 Glycobiology 16(8):757-65
This person is not on ResearchGate, or hasn't claimed this research yet.
This person is not on ResearchGate, or hasn't claimed this research yet.
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The bacterial hyaluronan lyases (Hyals) that degrade hyaluronan, an important component of the extracellular matrix, are involved in microbial spread. Inhibitors of these enzymes are essential in investigation of the role of hyaluronan and Hyal in bacterial infections and constitute a new class of antibiotics against Hyal-producing bacteria. Recently, we identified 1,3-diacetylbenzimidazole-2-thione and related molecules as inhibitors of streptococcal Hyal. One of such compounds, 1-decyl-2-(4-sulfamoyloxyphenyl)-1-indol-6-yl sulfamate, was co-crystallized in a complex with Streptococcus pneumoniae Hyal and its structure elucidated. The resultant X-ray structure demonstrates that this inhibitor fits in the enzymatic active site via interactions resembling the binding mode of the natural hyaluronan substrate. X-ray structural analysis also indicates binding interactions with the catalytic residues and those of a catalytically essential hydrophobic patch. An IC50 value of 11 microM for Hyal from Streptococcus agalactiae (strain 4755) qualifies this phenylindole compound as one of the most potent Hyal inhibitors known to date. The structural data suggested a similar binding mode for N-(3-phenylpropionyl)-benzoxazole-2-thione. This new compound's inhibitory properties were confirmed resulting in discovery of yet another Hyal inhibitor (IC50 of 15 microM). These benzoxazole-2-thiones constitute a new class of inhibitors of bacterial Hyals and are well suited for further optimization of their selectivity, potency, and pharmacokinetic properties.
... IC 50 Values (mM) 2, 4-Dichlorophenoxy acetic acid dimethylamine salt 0.3101 Enrofloxacin 0.4276 Rigden et al. (2006) show that sulfamoyloxy group forms a network of hydrogen bonding interactions with protein and water. The interactions associated with the charge-assisted bidentate H bonds between Arg466 and the two-sulfamoyl oxygen atoms. ...
... Moreover, there is only a single direct H bond of a sulfamoyl oxygen with the indole NH of Trp292. In this case, a water molecule mediates additional interactions with the carboxylate of Asp352 (Rigden et al., 2006) . ...
In this study, the in vitro effects of enrofloxacin, a broad spectrum antibiotic, and 2, 4-Dichlorophenoxy acetic acid dimethylamine salt that, a herbicide, on the bovine testicular hyaluronidase (BTH) were analyzed. BTH was purified using the method of ammonium sulfate precipitation and using affinity gel (Sepharose-4B-L-tyrosine-m-anisidine). Then the inhibiting effects of enrofloxacin and 2, 4-Dichlorophenoxy acetic acid dimethylamine salt on the purified BTH enzyme were identified. IC50 values of these chemical substances were found to be 0.3101 and 0.4276 mM, respectively.
... The central chromophoric unit of MC 540 is a benzoxazole moiety . Literature shows that the benzoxazole derivatives play an important role in medicinal as well as in industrial chemistry as the parent moiety itself bears antidepressant, antibacterial, antifungal , anti-inflammatory and anticancer activities 8 91011121314. The proton donor and/or acceptor abilities of N-heteroatom make benzoxazole derivatives biologically active. ...
... The proton donor and/or acceptor abilities of N-heteroatom make benzoxazole derivatives biologically active. The complex between benzoxazole derivatives and enzymes like kinases or other proteins are stabilized by hydrogen bonding through nitrogen atom along with p-stacking 8 91011. Most of the complexes of benzoxazole derivatives are neutral in character; however MC 540, the drug of our interest, is anionic in nature. ...
... Further, in view of improving the stability and shelf life of synthesized compounds, the benzimidazole was substituted by a benzoxazole skeleton. In order to get the insight in to the binding mode of benzoxazole derivatives, the X-ray structure of the related S. pneumoniae HA lyase (SpnHL) co-crystallized with an alkyl-2-phenylindole derivative, 1-decyl-2-(4sulfamoyloxyphenyl)-1H-indol-6-yl-sulfamate was used [171] . It was found that the inhibitor fits in the active site of HA lyase via hydrophobic interactions similar to the binding mode of HA. ...
The hyaluronidases (HAases) are a group of less extensively studied glycosidases distributed throughout the animal kingdom and are popularly known as 'spreading factors'. In recent years, HAases received much attention due to their ability to abruptly alter the hyaluronic acid (HA) homeostasis. HAases preferentially degrade HA, which is a megadalton acidic structural polysaccharide found exclusively in the extracellular matrix (ECM) of animals. The HA-HAase system has been suggested to participate in many pathophysiological conditions. The HA degradation in ECM, crack down the structural integrity with an eventual increased tissue permeability that is attributed for the spreading property. The spreading property has been widely accepted in functions including envenomation, acrosomal reaction/ovum fertilization, cancer progression, microbial pathogenesis such as wound infections, pneumonia, and other sepses like, bacteremia and meningitis. HA fragmentation has dual effects; generation of a wide molecular range bioactive oligosaccharides of angiogenic, pro-inflammatory, and immunostimulatory properties; and impairment in the reservoir capacity of ECM that holds metal ions, growth factors, cytokines and various enzymes for signal transduction. Hence, inhibition of HA degradation appears critical and imperative in HAase mediated pathological conditions. HAase inhibitors are thus potent regulators that maintain HA homeostasis and they might serve as anti-inflammatory, anti-aging, anti-microbial, anticancer and anti-venom/toxin and contraceptive agents. In addition, HAase inhibitors may serve as tools to understand several unexplained and complex functions of HAases in HA metabolism. Therefore, this review is expected to provide an integrated update as of 2008 on the HAase inhibitors and their possible role as therapeutics in the management of a wide range of pathological conditions.
... Makrocząsteczki kwasu hialuronowego, stanowiącego jeden z głównych składników macierzy pozakomórkowej tkanek zwierzęcych, oddziałują także z obecnymi w macierzy glikoproteinami, takimi jak fi bronektyna, laminina oraz z białkami włóknistymi -kolagenem czy elastyną [57, 73]. ...
Hyaluronan (HA) is a nonsulfated nonepimerized linear glycosaminoglycan (GAG) existing in vivo as a polyanion of hyaluronic acid and composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine [-->4GlcAbeta1-->3GlcNAcbeta1-->]. It is a major constituent of the extracellular matrix (ECM) of the skin, joints, eye, and many other tissues and organs.The simple structure of this ubiquitous macromolecule belies the complexity of its physico-chemical properties and biological functions, which depend on HA's molecular weight and interacting molecules called "hyaladherins". HA has extraordinary hydrophilic, rheological, and signaling properties and is viscoelastic. This naturally occurring biopolymer is dynamically involved in many biological processes, such as embryogenesis, inflammation, metastasis, tumor progression, tissue turnover, and wound healing. Wound healing is a dynamic interactive process involving many precisely interrelated phases, overlapping in time and leading to the restoration of tissue integrity. The healing process reflects the complex and coordinated body response to tissue injury resulting from the interaction of different cell types and extracellular matrix components. Hyaluronan plays a key role in each phase of wound healing by stimulating cell migration, differentiation,and proliferation as well as regulating ECM organization and metabolism.
... Small moleculebased inhibitor design strategies also target specific residues within the active site that are known to be crucial for catalysis. Targeting of these sites in the enzyme has been reported to add to the potency of inhibition (43) . These reports add strength to our data because many of the reported crucial groups of residues were observed to be blocked by the inhibitor HABP1 in the final refined model as follows. ...
Bacterial hyaluronan lyase enzymes are the major virulence factors that enable greater microbial ingress by cleaving hyaluronan
(HA) polymers present predominantly in extracellular space of vertebrates. Based on the premise that effective inhibitors
may bind to and stabilize HA thereby protecting it from degradation, here we investigated inhibitory activity of human hyaluronan-binding
protein 1 (HABP1) on bacterial hyaluronidase because it is highly specific to HA and localized on the cell surface. Biochemical
characterization revealed that HABP1 is a competitive inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL) with an IC50 value of 22 μm. This is thus the first report of an endogenous protein inhibitor that may be used during natural antibacterial defense.
Our findings also support a novel multipronged mechanism for the high efficacy of HABP1-mediated inhibition based on structural
modeling of enzyme, substrate, and inhibitor. Evidence from docking simulations and contact interface interactions showed
that the inherent charge asymmetry of HABP1 plays a key role in the inhibitory activity. This novel role of HABP1 may pave
the way for peptide inhibitors as alternatives to synthetic chemicals in antibacterial research.
... Buschauer and collaborators identified 1,3-diacetylbenzimidazole- 2-thione, 1-decyl-2-(4-sulfamoyloxyphenyl)-1H-indol-6-yl sulfamate [12] and N-substituted benzoxazole-2-thione derivatives as inhibitors of streptococcal Hyal. Several of them showed high hyaluronidase inhibitor activity especially against hyaluronidase derived from Streptococcus agalactiae [13, 14] . Structures and IC 50 values of these compounds are shown inTable 1. Olgen et al. found that the inhibition hyaluronidase activity of indole-2-and 3-carboxamide derivatives was found to be slightly different. ...
We have synthesized twelve 2-substituted benzimidazole, benzothiazole and indole derivatives using on both microwave irradiation and conventional heating methods. The microwave method was observed to be more beneficial as it provides an increase of yield from 3% to 113% and a 95 to 98 % reduction in time. All compounds were tested by a stains-all assay at pH 7 and by a Morgan-Elson assay at pH 3.5 for hyaluronidase inhibitory activity at a concentration of 100 microM. The most potent compound was 2-(4-hydroxyphenyl)-3-phenylindole (12) with an IC(50) value of 107 microM at both pH 7 and 3.5.
Streptococcus suis serotype 2 (S. suis 2) is an important pathogen of zoonoses. However, the role of virulence factor in pathogenesis of S. suis 2 is still uncertain. More and more attentions are paid in investigating other virulence-related genes in recent years. This paper reviews the progress in research on novel virulence-related gene of S. suis 2.
Infections caused by Streptococcus pneumoniae (pneumococcus) are a major cause of mortality throughout the world. This bacteria is a causative agent for community acquired pneumonia, bacteremia, acute otitis media, and meningitis. Its major disease burden is in children, the elderly, and patients with HIV and other immuno-suppressive conditions. The 23-valent capsular polysacchride vaccine is useful in adults but fails to protect those at highest risk of disease at the youngest and oldest ages. Although the current 7-valent conjugate vaccine is effective against invasive diseases caused by the vaccine-type strains, however, S. pneumoniae can be divided into more than 90 serotypes according to the immunochemistry of their capsular polysaccharide, so the vaccine coverage could be limited by invasive nonvaccine-serotypes in vaccinated individuals. Several pneumococcal proteins have been under investigation as potential vaccine candidates including pneumococcal surface protein A (PspA), which is a virulence factor expressed by all clinical S. pneumoniae isolates. This review summarizes some of antigenic determinants that are being studied in the level of experimental models and/or clinical trials for their potential to induce protective immune responses. Some of these markers are located on the bacterial cell surface and anchored to the cell surface structures by well-characterized mechanisms.
Carbon-donated hydrogen bonds (CDHBs) are weak forms of hydrogen bonding (0.5-1.0 kcal mol(-1) ) that are difficult to detect, and thus their roles in the structure and functionality of chemical systems often go unrecognized. Utilizing a computational approach, the existence of a structurally significant CDHB in the medically relevant protein Streptococcus pneumoniae hyaluronate lyase (SpnHL) is affirmed. The structure of a tetrapeptide fragment model containing the CDHB was optimized with second-order perturbation theory. From this, a CDHB with bond distance and angle consistent with previously discovered CDHBs and comparable to neighboring traditional HBs in the fragment model was found. The CDHB competes with another donor T253 OH, whereby the two alternate in strength between protein conformations, imbuing αHelix 3 appreciable flexibility. The CDHB seems to exist in spite of torsional and steric strain on the donor methyl group. It is postulated that the CDHB could aid in either counteracting the macrodipole of αHelix 3 or protecting the A249 CO from destabilizing interactions with the adjacent solvent. Employing the energy gradients from the optimization, the torque generated by the fragment model was computed, which accurately predicts the direction of rotation of αHelix 3 observed from experiment. A strongly correlated motion between αHelix 3 and αHelices 2, 4, and 5 was noted, which the interactions of the fragment model help drive by generating a torque much larger than necessary to rotate just αHelix 3. Considering these results, we conclude that CDHBs should be considered as possible beneficial components of chemical and biological phenomena.
The structures of two mutants (H192A and Y246F) of a mannuronate-specific alginate lyase, A1-III, from Sphingomonas species A1 complexed with a tetrasaccharide substrate [4-deoxy-L-erythro-hex-4-ene-pyranosyluronate-(mannuronate)(2)-mannuronic acid] were determined by X-ray crystallography at around 2.2 Å resolution together with the apo form of the H192A mutant. The final models of the complex forms, which comprised two monomers (of 353 amino-acid residues each), 268-287 water molecules and two tetrasaccharide substrates, had R factors of around 0.17. A large conformational change occurred in the position of the lid loop (residues 64-85) in holo H192A and Y246F compared with that in apo H192A. The lid loop migrated about 14 Å from an open form to a closed form to interact with the bound tetrasaccharide and a catalytic residue. The tetrasaccharide was bound in the active cleft at subsites -3 to +1 as a substrate form in which the glycosidic linkage to be cleaved existed between subsites -1 and +1. In particular, the O(η) atom of Tyr68 in the closed lid loop forms a hydrogen bond to the side chain of a presumed catalytic residue, O(η) of Tyr246, which acts both as an acid and a base catalyst in a syn mechanism.
This paper analyzes low-side active clamp forward converter with synchronous rectification (LACFC-SR) in detailed. Due to the additional clamp circuit composed of an auxiliary switch and clamp capacitor, the power transformer can be reset without the conventional tertiary winding. Moreover, the clamp circuit not only replaces the traditional RCD snubber circuit to mend spike current but also offers the main and auxiliary switches of the converter to achieve zero-voltage switching (ZVS). It reduces switching losses of the main and auxiliary switches. To deal with low voltage and high current output, the synchronous rectification is used to reduce conduction losses. A prototype of LACFC-SR with 30 ~ 60 V input and 5 V/ 20 A output has been implemented to verify the theoretical analysis. The power transfer efficiency is improved by the achievement of ZVS and synchronous rectification.
Bacterial hyaluronan lyases (Hyal) degrade hyaluronan, an important component of the extracellular matrix, and are involved in microbial spread. Hyal inhibitors may serve as tools to study the role of the enzyme, its substrates and products in the course of bacterial infections. Moreover, such enzyme inhibitors are potential candidates for antibacterial combination therapy. Based on crystal structures of Streptococcus pneumoniae Hyal in complex with a hexasaccharide substrate and with different inhibitors, 1-acylated benzimidazole-2-thiones and benzoxazole-2-thiones were derived as new leads for the inhibition of Streptococcus agalactiae strain 4755 Hyal. Structure-based optimization led to N-(3-phenylpropionyl)benzoxazole-2-thione, one of the most potent compounds known to date (IC(50) values: 24 μM at pH 7.4, 15 μM at pH 5). Among the 27 new derivatives, other N-acylated benzimidazoles and benzoxazoles are just as active at pH 7.4, but not at pH 5. The results support a binding mode characterized by interactions with residues in the catalytic site and with a hydrophobic patch.
Bacterial enzymatic degradation of glycosaminoglycans such as hyaluronan and chondroitin is facilitated by polysaccharide lyases. Family 8 polysaccharide lyase (PL8) enzymes contain at least two domains: one predominantly compos
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