Structure-Based Exploration of Cyclic Dipeptide Chitinase Inhibitors

Abstract

Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhibits family 18 chitinases by mimicking the structure of the proposed reaction intermediate. Here we report the high-resolution structures of four new CI-, and cyclo-(L-Tyr-L-Pro), in complex with a family 18 chitinase. In addition, details of enzyme inhibition and in vivo activity against Saccharomyces cerevisiae are presented. The structures reveal that the common cyclo-(Gly-Pro) substructure is sufficient for binding, allowing modification of the side chain of the nonproline residue. This suggests that design of cyclic dipeptides with a view to increasing inhibition of family 18 chitinases should be possible through relatively accessible chemistry. The derivatives presented here in complex with chitinase B from Serratia marcescens provide further insight into the mechanism of inhibition of chitinases by cyclic dipeptides as well as providing a new scaffold for chitinase inhibitor design.

Purification and identification of two antifungal cyclic dipeptides from Bacillus cereus subsp. thuringiensis associated with a rhabditid entomopathogenic nematode especially against Fusarium oxysporum

“…The linear form of the dipeptide is often less stable in vivo than its cyclic counterpart, therefore making the latter variety far more promising in terms of drug candidacy 36 . Both natural and synthetic diketopiperazines have a wide variety of biological activities, including antitumor 38 , antiviral 39 , antifungal 40 and antibacterial 41 . Especially, 2,5-diketopiperazines recently have attracted attention due to their biological properties 42 .…”

Antimycobacterial activity of cyclic dipeptides isolated fromBacillussp. N strain associated with entomopathogenic nematode

“…DKPs have long been disregarded; however, more recently they have received an increasing amount of attention in drug discovery (Krchnak et al, 1996). For both natural and synthetic DKPs, a wide variety of biological activities was reported, including antitumor (Milne et al, 1998;Nicholson et al, 2006), antiviral (Sinha et al, 2004), antifungal (Houston et al, 2004) and antibacterial (Kwon et al, 2000) activities.…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Overall, 2,5-diketopiperazine derivatives emerged in the last decade as very attractive molecules in drug discovery [204][205][206][207][208][209][210]. Indeed, these derivatives usually exhibit various biological properties [211], including antitumor [212,213] antiviral [214], antifungal [215,216] antibacterial [217,218] or antifouling activities [219]. Interestingly, their role in the bitter taste of coffee, beer, cacao and chocolate has been highlighted [220].…”