Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.

Abstract:

:Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.

journal_name

Nat Commun

journal_title

Nature communications

authors

Lama L,Adura C,Xie W,Tomita D,Kamei T,Kuryavyi V,Gogakos T,Steinberg JI,Miller M,Ramos-Espiritu L,Asano Y,Hashizume S,Aida J,Imaeda T,Okamoto R,Jennings AJ,Michino M,Kuroita T,Stamford A,Gao P,Meinke P,Glickman

doi

10.1038/s41467-019-08620-4

subject

Has Abstract

pub_date

2019-05-21 00:00:00

pages

2261

issue

1

issn

2041-1723

pii

10.1038/s41467-019-08620-4

journal_volume

10

pub_type

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