Design and synthesis of bis-carbamate analogs of cyclic bis-(3'-5')-diguanylic acid (c-di-GMP) and the acyclic dimer PGPG.
The bacterial second messenger cyclic bis-(3'-5')-diguanylic acid (c-di-GMP) regulates diverse Gram-negative bacterial virulence functions. The pathways that control, or are controlled by, c-di-GMP suggest that c-di-GMP signaling systems may encompass potential drug targets. It is presently undetermined, however, whether up- or down-modulation of c-di-GMP signaling would be the desired therapeutic state. We addressed potential drug target validation by synthesizing nonhydrolysable carbamate analogs of both the cyclic dinucleotide and the acyclic (seco) dinucleotide. A molecular docking simulation of the carbamate isostere suggests that this analog is capable of assuming the correct conformation and pose at a c-di-GMP binding site.
Kline
Toni
T
Department of Immunology, University of Washington, Seattle, Washington 98195,, USA. klinet@u.washington.edu
Jackson
Stona R
SR
Deng
Wei
W
Verlinde
Christophe L M J
CL
Miller
Samuel I
SI
D002219:Carbamates / Q000737:chemistry*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D019281:Dimerization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure
D002219:Carbamates; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP