Two-Prong Inhibitors for Human Carbonic Anhydrase II

Roy, B. C.; Banerjee, Ashim; Swanson, Michael; Jia, Xiao; Haldar, Manas K.; Mallik, Sanku; Srivastava, D. K.

doi:10.1021/ja047271k

Cited by 37 publications

(48 citation statements)

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“…28 The change in the absorbance values at different concentrations of nanoceria indicated the inhibiting effect of the conjugated nanoparticles. 8 The declining slopes in Figure 5 reveal that, when the inhibitor-functionalized nanoceria bound to the active site of hCAII, the rate of formation of 4-nitrophenolate from 4-nitrophenyl acetate decreased. 8 A decrease in the rate of its formation produced a solution that became tinted at a slower rate, which was represented by the decrease in the absorbance values as a function of time (see Figure 5).…”

Section: Functionalization Chemistry Using X-ray Photoelectron Spectrmentioning

confidence: 95%

“…5 Also, it is now extensively documented that significant enhancement of CA inhibition can be achieved through coupling the primary recognition aromatic sulfonamide motif with secondary binding elements. 3,[5][6][7][8][9] The mechanism for inhibition of hCAII by CBS involves coordination of the sulfonamide group (as the anion) to the zinc atom in the active site of hCAII to form a complex in an exothermic reaction. 6,10,11 In treating ophthalmic diseases such as glaucoma, conventional liquid eye drops is not a sufficient mode of therapy because of lachrymal drainage losses.…”

Section: Introductionmentioning

confidence: 99%

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Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

et al. 2007

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Human carbonic anhydrase (hCAII) is a metalloenzyme that catalyzes the reversible hydration of carbon dioxide to bicarbonate and is associated with glaucoma (a major cause of blindness). The present study focuses on the use of cerium oxide nanoparticles (nanoceria) as a potential delivery device for hCAII inhibitors. Carboxybenzenesulfonamide, an inhibitor of the hCAII enzyme, was attached to nanoceria particles using epichlorohydrin as an intermediate linkage. Along with the CA inhibitor, a fluorophore (carboxyfluorescein) was also attached on the nanoparticles to enable the tracking of the nanoparticles in vitro as well as in vivo. X-ray photoelectron spectroscopic studies carried out at each reaction step confirmed the successful derivatization of the nanoceria particles. The attachment of carboxyfluorescein was also confirmed by confocal fluorescence microscopy. Preliminary studies suggest that carboxybenzenesulfonamide-functionalized nanoceria retains its inhibitory potency for hCAII.

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Section: Functionalization Chemistry Using X-ray Photoelectron Spectrmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

et al. 2007

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“…The most successful bivalent arylsulfonamides have exploited contacts between the secondary recognition element and two hydrophobic patches in the conical cleft of CA II. 284,377,507,508,596 As mentioned in section 10.2.3, the mode of binding of the head group and the phenyl ring (the primary recognition element) of the psubstituted benzenesulfonamide is conserved with variation of the para-substituent; this consistent binding allows a direct evaluation of the influence of the secondary recognition element on affinity. (Table 10).…”

Section: General Approach: Addition Of a Secondary Recognition Elemenmentioning

confidence: 97%

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

et al. 2008

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I. Introduction to Carbonic Anhydrase (CA) and to the Review 948 1. Introduction: Overview of CA as a Model 948 1.1. Value of Models 950 1.2. Objectives and Scope of the Review 950 2. Overview of Enzymatic Activity 950 3. Medical Relevance 951 II. Structure and Structure−Function Relationships of CA 953 4. Global and Active-Site Structure 953 4.1. Structure of Isoforms 953 4.2. Isolation and Purification 954 4.3. Crystallization 954 4.4. Structures Determined by X-ray Crystallography and NMR 955 4.4.1. Structures Determined by X-ray Crystallography 955 4.4.2. Structure Determined by NMR 955 4.5. Global Structural Features 963 4.6. Structure of the Binding Cavity 964 4.7. Zn II -Bound Water 965 5. Metalloenzyme Variants 966 6. Structure−Function Relationships in the Catalytic Active Site of CA 968 6.1. Effects of Ligands Directly Bound to Zn II 968 6.2. Effects of Indirect Ligands 969 7. Physical-Organic Models of the Active Site of CA 969 III. Using CA as a Model to Study Protein−Ligand Binding 970 8. Assays for Measuring Thermodynamic and Kinetic Parameters for Binding of Substrates and Inhibitors 970 8.1. Overview 970 8.

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“…A similar approach has been adopted in the design of inhibitors of carbonic anhydrases I and II, in which a cupric iminodiacetate moiety is tethered to a sulfonamide group in order to simultaneously bind to the active site Zn 2+ ion and a histidine residue ~8 Å away (39)(40)(41).…”

Section: Structural Aspects Of Inhibitor Designmentioning

confidence: 99%

Binding of Uridine 5‘-Diphosphate in the “Basic Patch” of the Zinc Deacetylase LpxC and Implications for Substrate Binding^,

Gennadios

Christianson

2006

Biochemistry

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LpxC is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of lipid A, a vital component of the outer membrane of Gram-negative bacteria. Accordingly, the inhibition of LpxC is an attractive strategy for the treatment of Gram-negative bacterial infections. Here, we report the 2.7 Å resolution X-ray crystal structure of LpxC from Aquifex aeolicus complexed with uridine 5′-diphosphate (UDP), and the 3.1 Å resolution structure of LpxC complexed with pyrophosphate. The X-ray crystal structure of the LpxC-UDP complex provides the first view of interactions likely to be exploited by the substrate UDP group in the "basic patch" of the active site. The diphosphate group of UDP makes hydrogen bond interactions with strictly conserved residue K239 as well as solvent molecules. The ribose moiety of UDP interacts with partially conserved residue E197. The UDP uracil group hydrogen bonds with both the backbone NH group and the backbone carbonyl group of E160, and with the backbone NH group of K162 through an intervening water molecule. Finally, the α-phosphate and uracil groups of UDP interact with R143 and R262 through intervening water molecules. The structure of LpxC complexed with pyrophosphate reveals generally similar intermolecular interactions in the basic patch. Unexpectedly, diphosphate binding in both complexes is accompanied by coordination to an additional zinc ion, resulting in the identification of a new metal-binding site termed the E-site. The structures of the LpxC-UDP and LpxC-pyrophosphate complexes provide new insights regarding substrate recognition in the basic patch and metal ion coordination in the active site of LpxC.The zinc metalloenzyme UDP -{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) catalyzes the first irreversible step in the biosynthesis of lipid A ( Figure 1) (1-4), which is ultimately incorporated into the outer leaflet of the outer membrane of Gramnegative bacteria as the hydrophobic anchor of lipopolysaccharide (LPS) (5-9). 1 The exterior sheath of LPS serves as a protective barrier that resists penetration by many common antibiotics such as erythromycin (8)(9)(10)(11)(12)(13)(14). Importantly, lipid A is the toxic component of LPS that triggers a severe immune response to Gram-negative bacterial infections, which can lead to septic shock accompanied by acute hypotension, multiple organ failure, and death (15-18). Accordingly, inhibitors of LpxC and lipid A biosynthesis represent a potential treatment option for Gramnegative sepsis. † This work was supported by the National Institutes of Health grant GM49758. ‡ The atomic coordinates of LpxC complexed with uridine 5′-diphosphate and pyrophosphate have been deposited in the Protein Data Bank, www.rcsb.org, with accession codes 2IER and 2IES, respectively. *To whom correspondence should be addressed: Tel: 215-898-5714. Fax: 215-573-2201. E-mail: chris@sas.upenn.edu.. 1 Abbreviations: LpxC, UDP -{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase; LPS, lipopolysaccha...

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Two-Prong Inhibitors for Human Carbonic Anhydrase II

Cited by 37 publications

References 16 publications

Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

Binding of Uridine 5‘-Diphosphate in the “Basic Patch” of the Zinc Deacetylase LpxC and Implications for Substrate Binding^,

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Two-Prong Inhibitors for Human Carbonic Anhydrase II

Cited by 37 publications

References 16 publications

Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

Surface-Derivatized Nanoceria with Human Carbonic Anhydrase II Inhibitors and Fluorophores: A Potential Drug Delivery Device

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

Binding of Uridine 5‘-Diphosphate in the “Basic Patch” of the Zinc Deacetylase LpxC and Implications for Substrate Binding,

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Binding of Uridine 5‘-Diphosphate in the “Basic Patch” of the Zinc Deacetylase LpxC and Implications for Substrate Binding^,