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Solid Phase Synthesis of N-(3-hydroxysulfonyl)-L-homoserine Lactone Derivatives and their Inhibitory Effects on Quorum Sensing Regulation in Vibrio harveyi  

Kim, Cheol-Jin (Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey)
Park, Hyung-Yeon (Bio-Max Institute, Seoul National University)
Kim, Jae-Eun (Environment Group, Samsung Advanced Institute of Technology, Samsung Electronics Co.)
Park, Hee-Jin (School of Chemical and Biological Eng., Seoul National University)
Lee, Bon-Su (Department of Chemistry, College of Natural Science, Inha University)
Choi, Yu-Sang (Department of Pharmacy, College of Pharmacy, Pusan National University)
Lee, Joon-Hee (Department of Pharmacy, College of Pharmacy, Pusan National University)
Yoon, Je-Yong (School of Chemical and Biological Eng., Seoul National University)
Publication Information
Microbiology and Biotechnology Letters / v.37, no.3, 2009 , pp. 248-257 More about this Journal
Abstract
The inhibitors against Vibrio harveyi quorum sensing (QS) signaling were developed by modifying the molecular structure of the major signal, N-3-hydroxybutanoyl-L-homoserine lactone (3-OH-$C_4$-HSL). A series of structural derivatives, N-(3-hydroxysulfonyl)-L-homoserine lactones (HSHLs) were synthesized by the solid-phase organic synthesis method. The in vivo QS inhibition by these compounds was measured by a bioassay system using the V. harveyi bioluminescence, and all showed significant inhibitory effects. To analyze the interaction between these compounds and LuxN, a 3-OH-$C_4$-HSL receptor protein of V. harveyi, we tentatively determined the putative signal binding domain of LuxN based on the sequence homology with other acyl-HSL binding proteins, and predicted the partial 3-D structure of the putative signal binding domain of LuxN by using ORCHESTRA program, and further estimated the binding poses and energies (docking scores) of 3-OH-$C_4$-HSL and HSHLs within the domain. In comparison of the result from this modeling study with that of in vivo bioassay, we suggest that the in silica interpretation of the interaction between ligands and their receptor proteins can be a valuable way to develop better competitive inhibitors, especially in the case that the structural information of the protein is limited.
Keywords
Quorum sensing inhibitors; autoinducer (AI-1); N-(3-hydroxysulfonyl)-L-homoserine lactone (HSL); Vibrio harveyi;
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