Nucleosides Nucleotides Nucleic Acids. 2008 Dec;27(12):1282-300.

Design and synthesis of bis-carbamate analogs of cyclic bis-(3'-5')-diguanylic acid (c-di-GMP) and the acyclic dimer PGPG.

Kline T, Jackson SR, Deng W, Verlinde CL, Miller SI.

Source

Department of Immunology, University of Washington, Seattle, Washington 98195,, USA. klinet@u.washington.edu

Abstract

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.

PMID:: 19003573; [PubMed - indexed for MEDLINE]

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Research Support, N.I.H., Extramural

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U54 A105714/PHS HHS/United States

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