Delving into the Latest Updates on cGAS(Twentyeight-Seven) with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms-

Target

CGAS

Action

modulators

Mechanism

CGAS modulators(cyclic GMP-AMP synthase modulators)

Therapeutic Areas

Immune System Diseases

Active Indication

Autoimmune Diseases

Inactive Indication-

Originator Organization

Redona Therapeutics, Inc.

Active Organization

Redona Therapeutics, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

In mammals, cyclic GMP-AMP synthase (cGAS) senses cytosolic dsDNA to trigger type I interferon (IFN) response via the sting signalling, but its regulatory role in fish remains unclear. In the present study, cGAS and cGAS-like (cGASL) were identified in the snakehead (Channa argus), but they differ in the organization of two domains, NTase domain, MAB21 domain, with an additional transmembrane domain in cGASL. It is further revealed that cGAS can bind with Sting to enhance the production of type I IFN and IFN-stimulated genes (ISGs), such as viperin, mx, and its entire molecule with all domains is necessary for its functioning. However, the co-transfection of cGAS or cGASL with tbk1 and mda5 inhibited the expression of ISGs in EPC cells. It is notable that cGAS may exhibit dual functionality either by promoting sting-dependent IFN response or by suppressing RLR pathway activation, whereas cGASL solely acted as an RLR pathway inhibitor. These findings reveal complexed, pathway-specific immunoregulatory roles of cGAS/cGASL in fish antiviral immunity.

01 Jul 2025·Asian Pacific journal of cancer prevention : APJCP

Molecular Docking and Dynamic Studies of Chlorogenic Acid Isomers as Antagonists of p53 Transcription Factor for Potential Adjuvant Radiotherapy

Article

Author: Sanjaya, Muhammad Fajar ; Purwanti, Tri ; Perkasa, Dian Pribadi ; Darwin, Darmawan ; Sugoro, Irawan ; Indryati, Suci

OBJECTIVE:

Chlorogenic acids (CGAs) are among potential natural radioprotectant for inhibiting inappropriate p53 activation of adjacent normal tissues upon radiotherapy. However, previous studies are mainly focused on 5-O-caffeoylquinic acid (5CGA). In this study, the antagonist role of three CGAs isomers against p53 protein is assed for potential anti-apoptotic activity using molecular docking and dynamic experiments.

METHODS:

The physicochemical and pharmacokinetic profile three CGA isomers (3-O-caffeoylquinic acid (3CGA), 4-O-caffeoylquinic acid (4CGA), and 5CGA) were predicted using SwissADME web. Subsequently, they were subjected to docking using AutoDock software against to p53's L1/S3 pocket. The best binding pose was advanced to molecular dynamic (MD) simulation spanning 5 ns to evaluate the time dependent stability using Visual Dynamic web.

RESULTS:

The SwissADME prediction showed that the position of esterification on quinic moiety had no impact on the physicochemical and pharmacokinetic of CGA isomers. They only violated one out of five Lipinski's rules with the Abbot's bioavailability score of 0.11. The docking results revealed that the 4CGA has the highest binding energy (-5.41 kCal/mol) on L1/S3 pocket of p53 protein followed by 5CGA (-4.81 kCal/mol) and 3CGA (-4.62 kCal/mol). The MD simulation showed that the p53 complex with each CGA isomers had a root mean square deviation of less than 0.25 nm and a radius gyration that of close to reference apoprotein. Importantly, fluctuation of important residues at L1/S3 pocket was decrease through complex formation with 3CGA (at His155 and Ser121) and 4CGA (Lys120 and Ser121).

CONCLUSION:

The CGA isomers satisfy the drug-likeness for a potential oral medicine. They potentially play role as anti-apoptotic agent through binding with p53's pocket that involves in DNA transcriptional activity. Among them, the 4CGA possess the highest potential due to its highest free binding affinity and its ability to stabilize the residues fluctuation in L1/S3 pocket.

01 Aug 2024·METABOLISM-CLINICAL AND EXPERIMENTAL

cGAS suppresses β-cell proliferation by a STING-independent but CEBPβ-dependent mechanism

Article

Author: Wu, Yan ; Ji, Yujiao ; Hu, Shanbiao ; Zhong, Jiaxin ; Luo, Hairong ; Yang, Yan ; Luo, Jing ; Zhang, Jingjing ; Li, Ting ; Cai, Zixin ; Liu, Feng

AIMS/HYPOTHESIS:

cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes.

METHODS:

Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGAS^βKO) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing.

RESULTS:

cGAS expression is upregulated in the islets of diabetic mice and by high glucose treatment in MIN6 cells. Both global cGAS deficiency and β-cell-specific cGAS knockout mice lead to improved glucose tolerance by promoting β-cell mass. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS- but not STING-deficiency leads to reduced expression of CEBPβ, a known suppressor of β-cell proliferation, concurrently with increased β-cell proliferation. Moreover, overexpression of CEBPβ reverses the upregulation of Cyclin D1 and D2 induced by cGAS deficiency, thereby regulating β-cell proliferation. These results confirm that cGAS regulation of β-cell proliferation via a CEBPβ-dependent but STING-independent mechanism.

CONCLUSIONS/INTERPRETATION:

Our findings highlight the pivotal role of cGAS in promoting β-cell proliferation and maintaining glucose homeostasis, potentially by regulating CEBPβ expression in a STING-independent manner. This study uncovers the significance of cGAS in controlling β-cell mass and identifies a potential therapeutic target for enhancing β-cell proliferation in the treatment of diabetes.

100 Deals associated with cGAS(Twentyeight-Seven)

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