Astin C

From Cyanodermella asteris

Astin C is a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs, inhibits intracellular DNA-induced Ifnb expression with IC50 of 3.42 and 10.83 uM for mouse embryonic fibroblasts (MEFs) and IMR-90 cells; does not affect the expression of IL6 mRNA induced upon treatment with TLR agonists poly(I:C), lipopolysaccharide (LPS), or R837; specifically binds to the C-Terminal Domain of STING (Kd=10 uM, both STING R232 and STING H232); suppresses the recruitment of IRF3 onto the STING signalosome, attenuates host antimicrobial defenses against HSV-1 and listeria monocytogenes, alleviates the autoinflammatory responses in vivo.

Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus.[Pubmed:31811021]

Proc Natl Acad Sci U S A. 2019 Dec 6. pii: 1910527116.

Medicinal plants are a prolific source of natural products with remarkable chemical and biological properties, many of which have considerable remedial benefits. Numerous medicinal plants are suffering from wildcrafting, and thus biotechnological production processes of their natural products are urgently needed. The plant Aster tataricus is widely used in traditional Chinese medicine and contains unique active ingredients named astins. These are macrocyclic peptides showing promising antitumor activities and usually containing the highly unusual moiety 3,4-dichloroproline. The biosynthetic origins of astins are unknown despite being studied for decades. Here we show that astins are produced by the recently discovered fungal endophyte Cyanodermella asteris We were able to produce astins in reasonable and reproducible amounts using axenic cultures of the endophyte. We identified the biosynthetic gene cluster responsible for astin biosynthesis in the genome of C. asteris and propose a production pathway that is based on a nonribosomal peptide synthetase. Striking differences in the production profiles of endophyte and host plant imply a symbiotic cross-species biosynthesis pathway for Astin C derivatives, in which plant enzymes or plant signals are required to trigger the synthesis of plant-exclusive variants such as astin A. Our findings lay the foundation for the sustainable biotechnological production of astins independent from aster plants.

Astin C Production by the Endophytic Fungus Cyanodermella asteris in Planktonic and Immobilized Culture Conditions.[Pubmed:31161690]

Biotechnol J. 2019 Aug;14(8):e1800624.

The fungal endophyte Cyanodermella asteris (C. asteris) has been recently isolated from the medicinal plant Aster tataricus (A. tataricus). This fungus produces Astin C, a cyclic pentapeptide with anticancer and anti-inflammatory properties. The production of this secondary metabolite is compared in immobilized and planktonic conditions. For immobilized cultures, a stainless steel packing immersed in the culture broth is used as a support. In these conditions, the fungus exclusively grows on the packing, which provides a considerable advantage for Astin C recovery and purification. C. asteris metabolism is different according to the culture conditions in terms of substrate consumption rate, cell growth, and Astin C production. Immobilized-cell cultures yield a 30% increase of Astin C production, associated with a 39% increase in biomass. The inoculum type as spores rather than hyphae, and a pre-inoculation washing procedure with sodium hydroxide, turns out to be beneficial both for Astin C production and fungus development onto the support. Finally, the influence of culture parameters such as pH and medium composition on Astin C production is evaluated. With optimized culture conditions, Astin C yield is further improved reaching a five times higher final specific yield compared to the value reported with Astin C extraction from A. tataricus (0.89 mg g(-1) and 0.16 mg g(-1) respectively).

The Cyclopeptide Astin C Specifically Inhibits the Innate Immune CDN Sensor STING.[Pubmed:30566866]

Cell Rep. 2018 Dec 18;25(12):3405-3421.e7.

cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that Astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with Astin C are more susceptible to HSV-1 infection. Consistently, Astin C markedly attenuates the autoinflammatory responses in Trex1(-/-) BMDM cells and in Trex1(-/-) mouse autoimmune disease model. Mechanistically, Astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.

Design and synthesis of plant cyclopeptide Astin C analogues and investigation of their immunosuppressive activity.[Pubmed:29871844]

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2523-2527.

To further investigate on the structure-activity relationships of immunosuppressive Astin C, seventeen analogues 1-17 were designed and synthetized via amino acid substitution strategy by the solid-phase peptide synthesis method for the first time. In comparison with Astin C (IC50=12.6+/-3.3muM), only compounds 2 (IC50=38.4+/-16.2muM), 4 (IC50=51.8+/-12.7muM), 5 (IC50=65.2+/-15.6muM), and 8 (IC50=61.8+/-12.4muM) exhibited immunosuppressive activity in the Lymph node cells of mice. These results showed that the Astin C analogues containing D-amino acid residues, hydrophobic long-chain alkyl substituents, and aryl substituents performed better than those carrying hydrophilic amino acid residues and short-chain alkyl substituents. Moreover compounds 15, 16, and 17 had no immunosuppressive activity, which suggested that cis-3,4-dichlorinated proline played an important role in the immunosuppressive activity of Astin C.

Simultaneous separation and determination of phenolic acids, pentapeptides, and triterpenoid saponins in the root of Aster tataricus by high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.[Pubmed:25491750]

J Sep Sci. 2015 Feb;38(4):571-5.

We established a qualitative method to analyze the main chemical compositions of the root of Aster tataricus. Most of the peaks were separated on a C(18) column packed with 5.0 mum particles, and 28 compounds were identified, including 11 chlorogenic acids, ten astins/asterinins, and seven astersaponins, four of which were reported for the first time from A. tataricus. Furthermore, we developed a reliable method for the simultaneous quantification of 3-caffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, astin A, astin B, Astin C, astersaponin A, and astersaponin C, and the qualified separations were achieved only on a C18 column packed with 2.7 mum particles. The method was used to measure the concentrations of eight components in samples from two major producing areas in China, and the average contents in samples from Bozhou (Anhui) were higher than those in samples from Anguo (Hebei).

Mitochondria-dependent apoptosis of activated T lymphocytes induced by astin C, a plant cyclopeptide, for preventing murine experimental colitis.[Pubmed:21569765]

Biochem Pharmacol. 2011 Aug 1;82(3):260-8.

Facilitating T-cell apoptosis is implicated as an effective therapeutic strategy for treatment of T cell-mediated disease, including inflammatory bowel disease. Here, we report that Astin C, a plant cyclopeptide isolated from the roots of Aster tataricus (Compositae), induced apoptosis of activated T cells in a mitochondria-dependent but Fas-independent manner in that such activity was still observed in T cells from Fas-mutated MRLlpr/lpr mice. Although caspase 8 was not activated, Astin C treatment led to the cleavage of caspase 9 and caspase 3, the upregulation of Bad protein expression as well as release of cytochrome c in activated T cells. Astin C did not induce the expression of GRP78 and GADD153, excluding involvement of endoplasmic reticulum stress-mediated pathway. Moreover, oral administration of Astin C protected mice against TNBS-induced colonic inflammation, as assessed by a reduced colonic weight/length ratio and histological scoring. Administering Astin C significantly decreased serum levels of TNF-alpha, IL-4 and IL-17, accompanied with the induction of apoptosis in activated T cells in vivo. The results demonstrate, for the first time, the ability of Astin C to induce apoptosis in activated T cells and its potential use in the treatment of colonic inflammation.

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