Bisdionin C—A Rationally Designed, Submicromolar Inhibitor of Family 18 Chitinases

Abstract

Chitinases of the GH18 family play important roles in a variety of pathogenic organisms and have also been shown to be involved in human asthma progression, making these enzymes potential drug targets. While a number of potent GH18 chitinase inhibitors have been described, in general, these compounds suffer from limited synthetic accessibility or unfavorable medicinal-chemical properties, making them poor starting points for the development of chitinase-targeted drugs. Exploiting available structural data, we have rationally designed bisdionin C, a submicromolar inhibitor of GH18 enzymes, that possesses desirable druglike properties and tractable chemical synthesis. A crystallographic structure of a chitinase-bisdionin C complex shows the two aromatic systems of the ligand interacting with two conserved tryptophan residues exposed in the active site cleft of the enzyme, while at the same time forming extensive hydrogen-bonding interactions with the catalytic machinery. The observed mode of binding, together with inhibition data, suggests that bisdionin C presents an attractive starting point for the development of specific inhibitors of bacterial-type, but not plant-type, GH 18 chitinases.

How to target small cell lung cancer

“…Employing structural chitinase data, the inhibitor bisdionin C which shows activity in the submicromolar range against GH18 enzymes was designed [ 87 ]. A crystallographic structure of a chitinase-bisdionin C complex demonstrated that two aromatic systems of the ligand block two conserved tryptophan residues of the active site chitinases.…”

Screening‐based discovery of Aspergillus fumigatus plant‐type chitinase inhibitors

“…Further exploration of chitinases as potential antifungal targets requires new potent chemical tools for the plant-type subclass to complement the nanomolar inhibitor, bisdionin C, discovered for Af ChiB [39] . To identify new Af ChiA1 inhibitor scaffolds, a HTS was performed using a fluorescent assay.…”

“…An aromatic group stacking with the active site tryptophan side chain (Trp312 in Af ChiA1, Trp285 in Sc CTS1) is a feature common to both compound 1 and acetazolamide as well as numerous other family 18 chitinase inhibitors [26] . Consequently, the absence of stacking moieties in compound 5 is unusual, though it may help explain the specificity of this molecule for plant-type over bacterial-type family 18 chitinases, as the latter group generally possesses a second tryptophan that forms a ‘lid’ for the active site [39] . Bacterial-type chitinase inhibitors generally bind sandwiched between the two Trp side chains, suggesting that these enzymes may have a stronger preference for flat/aromatic ligands.…”

“…Chitinases represent a fascinating group of enzymes from a chemical perspective although their precise physiological roles remain elusive. In particular, the bacterial-type family have been extensively studied in terms of competitive inhibitors that mimic the carbohydrate substrate interaction [39,42,43]. Although both a natural product cyclopentapeptide inhibitor (argifin [43]) and a synthesised derivative based on linking a two-xanthine ring system (bisdionin C [39]) have high nanomolar affinities for AfChiB they provide limited starting-points for plant-type chitinase inhibitors [23].…”

Structural dissection reveals a general mechanistic principle for group II chitinase (ChtII) inhibition

“…Cyclic peptide-based inhibitors, such as argifin, argadin, and their derivatives, mimic the carbohydrate-protein interactions (16 -21). By virtual screening, other inhibitors were also obtained, including methylxanthine derivatives (22)(23)(24), closantel derivatives (25,26), berberine (27), styloguanidine (28) and psammaplins (29). These compounds exhibit inhibitory activities at nanomolar to millimolar levels.…”