Synthesis of allosamidin analogues

Blattner, R.; Furneaux, Richard H.; Lynch, Greg P.

doi:10.1016/s0008-6215(96)90613-8

Cited by 22 publications

(13 citation statements)

References 24 publications

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“…It was isolated from the mycelium of Streptomyces sp. and exhibits a strong inhibitory activity against family 18 chitinases of insects and fungi with a Ki in the nano-to micromolar range (Sakuda et al, 1987;Blattner et al, 1996;Berecibar et al, 1999). Most strikingly, it blocks malaria parasite transmission by inhibiting the chitinase of Plasmodium that is essential to penetrate the host's peritrophic matrix (Shahabuddin et al, 1993;Tsai et al, 2001;Filho et al, 2002).…”

Section: Inhibition Of Chitin Metabolismmentioning

confidence: 99%

Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases

Merzendorfer

Zimoch

2003

Journal of Experimental Biology

1,051

845

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SUMMARY Chitin is one of the most important biopolymers in nature. It is mainly produced by fungi, arthropods and nematodes. In insects, it functions as scaffold material, supporting the cuticles of the epidermis and trachea as well as the peritrophic matrices lining the gut epithelium. Insect growth and morphogenesis are strictly dependent on the capability to remodel chitin-containing structures. For this purpose, insects repeatedly produce chitin synthases and chitinolytic enzymes in different tissues. Coordination of chitin synthesis and its degradation requires strict control of the participating enzymes during development. In this review, we will summarize recent advances in understanding chitin synthesis and its degradation in insects.

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Section: Inhibition Of Chitin Metabolismmentioning

confidence: 99%

Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases

Merzendorfer

Zimoch

2003

Journal of Experimental Biology

1,051

845

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“…For example, inhibitors of family 18 glycoside hydrolases [which hydrolyse chitin, a polymer of β(1,4)linked N-acetylglucosamine] affect the life cycles of several fungi [2][3][4] and block transmission of the malaria parasite (Plasmodium falciparum) from host to insect vector [5,6]. The most potent inhibitor available, the pseudo-trisaccharide allosamidin, inhibits all family 18 chitinases, yet it is expensive and difficult to synthesize [7][8][9][10]. Although carbohydrate oligomers and their derivatives are good candidates for the design of glycoside hydrolase inhibitors, they are often difficult to synthesize and too large to cross cell membranes.…”

Section: Introductionmentioning

confidence: 99%

The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate

Houston

Eggleston

Synstad

et al. 2002

Biochemical Journal

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Family 18 chitinases are attractive targets for the development of new inhibitors with chemotherapeutic potential against fungi, insects and protozoan/nematodal parasites. Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. The structure reveals that the cyclic dipeptide inhibits chitinases by structurally mimicking a reaction intermediate, and could, on the basis of its accessible chemistry, be a candidate for further optimization.

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“…Unfortunately, total synthesis of allosamidin and its derivatives is difficult and expensive (25,26), making it a less suitable candidate for further optimization as a chemotherapeutical. Other natural products that inhibit family 18 chitinases have been reported such as the styloguanidines isolated from a marine sponge (27), cyclo(Arg-Pro) from marine bacteria (1,28), and the psammaplins isolated from a marine sponge (29).…”

mentioning

confidence: 99%

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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Synthesis of allosamidin analogues

Cited by 22 publications

References 24 publications

Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases

Chitin metabolism in insects: structure, function and regulation of chitin synthases and chitinases

The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate

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

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