Synthesis and Biological Activity of Allosamidin and Allosamidin Analogues

Blattner, R.; Gerard, P.J.; Spindler-Barth, Margarethe

doi:10.1002/(sici)1096-9063(199708)50:4<312::aid-ps594>3.0.co;2-o

Cited by 26 publications

(13 citation statements)

References 27 publications

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“…Thus, there appears to be scope for the development of allosamidin derivatives with differential specificity based on the changes around the Ϫ2 and Ϫ3 subsites. In this context, it is worth noticing that such derivatives have already been reported, although so far all changes in the allosamine sugars appear to reduce chitinase inhibition (39,41,42).…”

Section: Figmentioning

confidence: 94%

Structure of Human Chitotriosidase

Fusetti¹,

Moeller²,

Houston³

et al. 2002

Journal of Biological Chemistry

189

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Chitin hydrolases have been identified in a variety of organisms ranging from bacteria to eukaryotes. They have been proposed to be possible targets for the design of novel chemotherapeutics against human pathogens such as fungi and protozoan parasites as mammals were not thought to possess chitin-processing enzymes. Recently, a human chitotriosidase was described as a marker for Gaucher disease with plasma levels of the enzyme elevated up to 2 orders of magnitude. The chitotriosidase was shown to be active against colloidal chitin and is inhibited by the family 18 chitinase inhibitor allosamidin. Here, the crystal structure of the human chitotriosidase and complexes with a chitooligosaccharide and allosamidin are described. The structures reveal an elongated active site cleft, compatible with the binding of long chitin polymers, and explain the inactivation of the enzyme through an inherited genetic deficiency. Comparison with YM1 and HCgp-39 shows how the chitinase has evolved into these mammalian lectins by the mutation of key residues in the active site, tuning the substrate binding specificity. The soaking experiments with allosamidin and chitooligosaccharides give insight into ligand binding properties and allow the evaluation of differential binding and design of speciesselective chitinase inhibitors.

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Section: Figmentioning

confidence: 94%

Structure of Human Chitotriosidase

Fusetti¹,

Moeller²,

Houston³

et al. 2002

Journal of Biological Chemistry

189

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“…The most potent one, the pseudotrisaccharide allosamidin, is a natural product isolated from Streptomyces (3,12), with K i values that range from strong (0.48 nM) to relatively weak (3.1 M) inhibition (13,14). Allosamidin derivatives were able to kill Lucilia cuprina blowfly larvae in in vitro test systems after contact or feeding (15). Structural analyses of complexes with family 18 chitinases have shown that allosamidin mimics an oxazolinium ion reaction intermediate bound to subsites Ϫ3 through Ϫ1 (16,17).…”

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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“…EI 50 is the 50% ecdysis inhibition. Compound 1 and its derivatives highly increased mortality of the blowfly larvae (Lucilia cuprina) after contact applications or feeding tests 20 . In the webbing clothes moth Tineola bisselliella, consumption of allosamidin 1 resulted in larval mortality associated with severe morphological alterations (delayed growth and interrupted moulting) that occur during larval development 20 .…”

Section: Insecticidal and Antifungal Activitiesmentioning

confidence: 99%

“…So, they play the insecticidal and antifungal actions 20,34 . The pseudo-trisaccharide allosamidin 1 has a competitive inhibitory activity against chitinases at very low concentration.…”

Section: Insecticidal and Antifungal Activitiesmentioning

confidence: 99%

High-efficient synthesis and biological activities of allosamidins

Huang

Peng

Mei

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family-18 chitinases, and it is confirmed to have insecticidal and antifungal activities. But the synthesis of allosamidins is very difficult, and it is a challengeable subject. Allosamidins were synthesized in solid-liquid phase, total solid-phase and total liquid-phase, respectively. Solid-liquid phase method realizes the partial solid-phase synthesis of allosamidins. Total solid-phase method greatly simplifies the purification process. Total liquid-phase method shortens the synthetic steps of allosamidins. The insecticidal and antifungal activities of allosamidins were also reported herein.

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Synthesis and Biological Activity of Allosamidin and Allosamidin Analogues

Cited by 26 publications

References 27 publications

Structure of Human Chitotriosidase

Structure of Human Chitotriosidase

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

High-efficient synthesis and biological activities of allosamidins

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