Crystal Structures of Allosamidin Derivatives in Complex with Human Macrophage Chitinase

Abstract

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.

Interactions of a Family 18 Chitinase with the Designed Inhibitor HM508 and Its Degradation Product, Chitobiono-δ-lactone

“…Met-212 is conserved in family 18 chitinases and contributes to the formation of a hydrophobic pocket for the oxazolinium ion methyl group (Figs. 1 and 4) (11)(12)(13)22). It is possible that Met-212 could limit the affinity that might be achieved by further structure-based development of HM508-like inhibitors.…”

Fully Deacetylated Chitooligosaccharides Act as Efficient Glycoside Hydrolase Family 18 Chitinase Inhibitors

“…Most of these inhibitors resemble the structure of oxazolinium ion intermediates or mimic carbohydrate-protein interactions. The pseudotrisaccharide allosamidin, which was isolated from the Streptomyces sp., is the most effective inhibitor, with K i values at the nanomolar level (11)(12)(13)(14)(15)(16)(17)(18). The cyclopentapeptides argifin and argadin, which were isolated from the cultured broths of fungal strains Gliocladium sp.…”

Human chitotriosidase CHIT1 cross reacts with mammalian‐like substrates

“…The greater turnover of LacdiNAc is attributed to additional binding interactions since it contains two N-acetyl groups. Interactions with the N-acetyl group in the -2 subsite were seen in the crystal structure of CHIT1 in allosamidine inhibitor complexes [17,18]. The -2 subsite corresponds to the non-reducing end of LacNAc-TMR thus accounting for its lower reactivity compared to LacdiNAc-TMR which has an N-acetyl substituent in the -2 subsite.…”