title: Synthesis of Triazole-Linked Analogues of c-di-GMP and Their Interactions with Diguanylate Cyclase.
abstract: Cyclic di-GMP (c-di-GMP) is a widespread second messenger that plays a key role in bacterial biofilm formation. The compound's ability to assume multiple conformations allows it to interact with a diverse set of target macromolecules. Here, we analyzed the binding mode of c-di-GMP to the allosteric inhibitory site (I-site) of diguanylate cyclases (DGCs) and compared it to the conformation adopted in the catalytic site of the EAL phosphodiesterases (PDEs). An array of novel molecules has been designed and synthesized by simplifying the native c-di-GMP structure and replacing the charged phosphodiester backbone with an isosteric nonhydrolyzable 1,2,3-triazole moiety. We developed the first neutral small molecule able to selectively target DGCs discriminating between the I-site of DGCs and the active site of PDEs; this molecule represents a novel tool for mechanistic studies, particularly on those proteins bearing both DGC and PDE modules, and for future optimization studies to target DGCs in vivo.
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome , 00185 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernicola
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino , 62032 Camerino, MC, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torquati
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome , 00185 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome , 00185 Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giardina
authors.affiliation: Department of Science, University Roma Tre , 00154 Rome, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: Rampioni
authors.affiliation: Department of Science, University Roma Tre , 00154 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Messina
authors.affiliation: Department of Science, University Roma Tre , 00154 Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Leoni
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino , 62032 Camerino, MC, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino , 62032 Camerino, MC, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome , 00185 Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Rinaldo
authors.affiliation: Medicinal Chemistry Unit, School of Pharmacy, University of Camerino , 62032 Camerino, MC, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
authors.affiliation: Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome , 00185 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cutruzzolà
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D006147:Guanine / Q000737:chemistry; D007202:Indicators and Reagents; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D014230:Triazoles; D006147:Guanine; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP