There exist eighteen histone deacetylases (HDACs) in mammals, the “classical” Zn-dependent HDAC1-11, and the NAD⁺-dependent sirtuins (SIRT) 1-7. Sirtuins require NAD⁺ for their enzymatic activity and have been implicated in age-related pathologies.

However, it is not so clear concerning the influence of sirtuins on immune responses. Indeed, the anti-inflammatory activities always relate to SIRT1 and SIRT6.

In this article, we will introduce a potent  SIRT1 inhibitor, CHIC35.

CHIC35 is an analog of EX-527, it inhibits SIRT1 with an IC₅₀ of 0.124 µM. Additionally, CHIC35 shows selective inhibition against SIRT1 over SIRT2 (IC₅₀=2.8 µM) or SIRT3 (IC₅₀>100 µM).

Firstly, in vitro, CHIC-35 increases acetylation of histone H4 in BMDMs similar to Cambinol (200 μM). In a zebrafish model of CHARGE syndrome. CHIC-35 exhibits no significant difference in the survival of embryos at early stages.
Zebrafish embryos are microinjected with 2.4 ng of chd7 MO to develop to different stages of development. CHIC-35 exists in chd7 morphant embryos from 8hpf to 24hpf. Furthermore, CHIC-35 is removed at 24hpf, and embryos are incubated in fresh egg water until 4dpf. The chd7 morphant larvae have a severely reduced and disrupted pattern of cartilage elements in comparison to the control. Besides, CHIC-35 shows partial recovery in craniofacial cartilage elements.
At 4dpf, zebrafish embryos show a well-formed lower jaw in controls. While chd7 morphants exhibit a reduced lower jaw. Treatment with CHIC-35 rescues the expression of sox9a inchd7 morphants.
What’s more, nearly 30% of chd7 morphant embryos (24hpf to 72hpf) show a near-complete loss of isl2a expression in the cranial region. But the wild-type controls only exhibit 10% isl2a expression. As a result, CHIC-35 reduces this to 7.5% significantly. However, CHIC-35 shows no discernible effect on the enteric neurons marked by Tg.

In conclusion, CHIC-35, as a potent SIRT1 inhibitor, has anti-inflammatory effects. It can inhibit inflammatory and innate immune responses, and also can be used for CHARGE syndrome research.

Reference:

[1]. Jérôme Lugrin, et al. Biochim Biophys Acta. 2013 Jun;1833(6):1498-510
[2]. Zainab Asad, et al. Eur J Med Genet. 2020 Feb;63(2):103661.