Hyaluronan lyase (HL) is secreted by most strains of the human pathogen group B Streptococcus (GBS). HL is believed to be a bacterial virulence factor, since it cleaves the viscous polysaccharide hyaluronic acid (HA) found in host extracellular tissue, enhancing the spread and infectivity of the bacteria. We previously utilized a homology structural model for GBS HL, and performed in silico screening using commercially available compounds and the software FlexX (Tripos, Inc.) to identify, select, and evaluate the enzyme inhibition for about 50 commercial compounds. This resulted in the identification of the first known small molecule inhibitor of HL (IC50 = 300 µM). This compound is a diphenyl ether, and since related structures are not commonly available, we proposed a structure-activity study to determine minimum structural features for good activity. Toward this goal, the structures of three new diphenyl ethers were proposed. Progress towards the synthesis of these will be presented.
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