Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase

Autor: Evelien M Te Poele, Alwin M. Hartman, Lubbert Dijkhuizen, Anna K. H. Hirsch, Walid A. M. Elgaher, Varsha R. Jumde
Přispěvatelé: HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany., Host-Microbe Interactions, Chemical Biology 2
Jazyk: angličtina
Rok vydání: 2020
Předmět:
synthesis
010402 general chemistry
01 natural sciences
Biochemistry
drug discovery
Small Molecule Libraries
Structure-Activity Relationship
chemistry.chemical_compound
Bacterial Proteins
Very Important Paper
Drug Discovery
Dynamic combinatorial chemistry
Combinatorial Chemistry Techniques
General Pharmacology
Toxicology and Pharmaceutics
Surface plasmon resonance
Pharmacology
chemistry.chemical_classification
dynamic combinatorial chemistry
Bacteria
Full Paper
biology
010405 organic chemistry
Drug discovery
Chemistry
Organic Chemistry
Biofilm
Substrate (chemistry)
Glycoside
glycosides
Maltose
Surface Plasmon Resonance
Full Papers
Combinatorial chemistry
Anti-Bacterial Agents
0104 chemical sciences
Glucosyltransferases
biology.protein
Molecular Medicine
Glucosyltransferase
glucosyltransferase
Sugars
Protein Binding
Zdroj: ChemMedChem
International
Germany
ChemMedChem, 16(1):cmdc.202000222, 113-123. WILEY-V C H VERLAG GMBH
Chemmedchem
ISSN: 1860-7179
Popis: We applied dynamic combinatorial chemistry (DCC) to find novel ligands of the bacterial virulence factor glucosyltransferase (GTF) 180. GTFs are the major producers of extracellular polysaccharides, which are important factors in the initiation and development of cariogenic dental biofilms. Following a structure‐based strategy, we designed a series of 36 glucose‐ and maltose‐based acylhydrazones as substrate mimics. Synthesis of the required mono‐ and disaccharide‐based aldehydes set the stage for DCC experiments. Analysis of the dynamic combinatorial libraries (DCLs) by UPLC‐MS revealed major amplification of four compounds in the presence of GTF180. Moreover, we found that derivatives of the glucose‐acceptor maltose at the C1‐hydroxy group act as glucose‐donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (K D values of 0.4–10.0 mm) according to surface plasmon resonance. In addition, they were investigated for inhibitory activity in GTF‐activity assays. The early‐stage DCC study reveals that careful design of DCLs opens up easy access to a broad class of novel compounds that can be developed further as potential inhibitors.
Delay decay: Structure‐based design in combination with acylhydrazone‐based dynamic combinatorial chemistry (DCC) afforded inhibitors of glucansucrase (GS), the main virulence factor responsible for dental caries. DCC offered a facile pathway for finding the first hits of GS in the form of glucose‐ and maltose‐based acylhydrazones, mimicking the GS substrate.
Databáze: OpenAIRE
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