Argadin, a New Chitinase Inhibitor, Produced by Clonostachys sp. FO-7314.

Arai, Noriko; Shiomi, Kazuro; Yamaguchi, Yuuichi; Masuma, Rokuro; Iwai, Yuzuru; Turberg, Andreas; Kölbl, H.; Ōmura, Satoshi

doi:10.1248/cpb.48.1442

Cited by 105 publications

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“…Preliminary analyses of argadin and argifin effects on endochitinase activity from L. cuprina blowfly revealed inhibition in the nanomolar range, with argadin inhibiting at an IC 50 of 150 nM (4,5). We have determined the inhibition constants of argifin and argadin against ChiB, revealing that while allosamidin inhibits ChiB with a K i of 450 nM, argifin shows weaker inhibition (K i ϭ 33 M) and argadin shows Ϸ20-fold stronger inhibition (K i ϭ 20 nM) than allosamidin (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Chitinase inhibitors have shown activity against fungi including Candida albicans (1), insects (2)(3)(4)(5) and the human malaria parasite Plasmodium falciparum (6,7). Furthermore, a knockout experiment confirmed that P. falciparum chitinase is essential for insect invasion (8).…”

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confidence: 99%

“…1), that were isolated from Gliocladium and Clonostachys fungal cultures, respectively (4,5). When tested against a family 18 chitinase from the blowfly L. cuprina, IC 50 values were found to be in the 100 nM range for argifin (4) and in the 1 nM range for argadin (5).…”

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confidence: 99%

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High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate

Houston

Shiomi

Arai

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Over the past years, family 18 chitinases have been validated as potential targets for the design of drugs against human pathogens that contain or interact with chitin during their normal life cycles. Thus far, only one potent chitinase inhibitor has been described in detail, the pseudotrisaccharide allosamidin. Recently, however, two potent natural-product cyclopentapeptide chitinase inhibitors, argifin and argadin, were reported. Here, we describe highresolution crystal structures that reveal the details of the interactions of these cyclopeptides with a family 18 chitinase. The structures are examples of complexes of a carbohydrateprocessing enzyme with high-affinity peptide-based inhibitors and show in detail how the peptide backbone and side chains mimic the interactions of the enzyme with chitooligosaccharides. Together with enzymological characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The peptides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition constants. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.

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confidence: 99%

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High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate

Houston

Shiomi

Arai

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Chitin is not found in humans but plays a key role in the life cycles of several classes of human pathogens, such as fungi (1), nematodes (2), protozoan parasites (3), and insects (4). Several chitinase inhibitors with biological activity have been identified, such as allosamidin (5), styloguanidines (6), and the cyclic peptides CI-4 (7-9), argifin (10), and argadin (11,12). Allosamidin (see Fig.…”

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Crystal Structures of Allosamidin Derivatives in Complex with Human Macrophage Chitinase

Rao

Houston

Boot

et al. 2003

Journal of Biological Chemistry

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The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structurebased design of specific allosamidin derivatives.

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“…9), including the cyclic dipeptide CI-4 and related compounds (10,11), the cyclic pentapeptides argifin and argadin (12)(13)(14), and the pseudotrisaccharide allosamidin, a nanomolar inhibitor isolated from Streptomyces sp. (15).…”

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Screening-based Discovery and Structural Dissection of a Novel Family 18 Chitinase Inhibitor

Schüttelkopf

Andersen

Rao

et al. 2006

Journal of Biological Chemistry

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Family 18 chitinases play key roles in the life cycles of a variety of organisms ranging from bacteria to man. Very recently it has been shown that one of the mammalian chitinases is highly overexpressed in the asthmatic lung and contributes to the pathogenic process through recruitment of inflammatory cells. Although several potent natural product chitinase inhibitors have been identified, their chemotherapeutic potential or their use as cell biological tools is limited due to their size, complex chemistry, and limited availability. We describe a virtual screening-based approach to identification of a novel, purine-based, chitinase inhibitor. This inhibitor acts in the low micromolar (K i ‫؍‬ 2.8 ؎ 0.2 M) range in a competitive mode. Dissection of the binding mode by x-ray crystallography reveals that the compound, which consists of two linked caffeine moieties, binds in the active site through extensive and not previously observed stacking interactions with conserved, solvent exposed tryptophans. Such exposed aromatics are also present in the structures of many other carbohydrate processing enzymes. The compound exhibits favorable chemical properties and is likely to be useful as a general scaffold for development of pan-family 18 chitinase inhibitors.Family 18 chitinases (CAZy GH 18) hydrolyze chitin, a homopolymer of ␤-(1,4)-linked N-acetylglucosamine. Chitin is a key component of the fungal cell wall, and chitinases are thought to be required for fungal cell separation and morphogenesis (2-4). Strikingly, whereas chitin does not occur in humans, it is known that we possess two chitinases (5, 6). Human macrophage chitotriosidase (HCHT) 4 is secreted by activated macrophages and is able to degrade chitin from the cell wall of the fungal pathogen Candida albicans. Although its precise role has not been defined, it has been shown to be upregulated during fungal or bacterial infection (7) and Gaucher disease, a lysosomal storage disorder (8). A second chitinase, termed acidic mammalian chitinase was subsequently discovered and shown to possess an unusually low pH optimum (Ͻ3) (6), and its overexpression in the lung has been linked to the progression of asthma.Most known family 18 chitinase inhibitors are natural products (reviewed in Ref. 9), including the cyclic dipeptide CI-4 and related compounds (10, 11), the cyclic pentapeptides argifin and argadin (12)(13)(14), and the pseudotrisaccharide allosamidin, a nanomolar inhibitor isolated from Streptomyces sp. (15). Their poor synthetic accessibility and limited availability from natural sources has so far hampered the use of these inhibitors for in vivo studies, whereas their chemical complexity makes them unsuitable as starting points for ligand design efforts. Nevertheless, numerous crystallographic and biochemical studies have elucidated the interactions between these compounds and family 18 chitinases (e.g. Refs. 11,14,[16][17][18].Recently, a high throughput screen identified three xanthine derivatives, theophylline, caffeine, and pentoxifylline, as competi...

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Argadin, a New Chitinase Inhibitor, Produced by Clonostachys sp. FO-7314.

Cited by 105 publications

References 0 publications

High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate

High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate

Crystal Structures of Allosamidin Derivatives in Complex with Human Macrophage Chitinase

Screening-based Discovery and Structural Dissection of a Novel Family 18 Chitinase Inhibitor

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