Andrographolide derivative as antagonist of vitamin D receptor to induce lipidation of microtubule associate protein 1 light chain 3 (LC3). (1st December 2021)

• Record Type: Journal Article
• Authors: Ding, Mo-Yu; Peng, Yuran; Li, Feng; Li, Zheng-Qing; Wang, Decai; Zhou, Guo-Chun; Wang, Ying
• Is Part Of: Bioorganic & medicinal chemistry. Volume 51(2021)
• Publication Date: 2021-12-01
• Subjects: Andrographolide derivative -- vitamin D receptor -- Microtubule associated protein 1 light chain 3 -- Lipidation -- Parkinsonism; Atg7 autophagy related 7 -- LC3 microtubule associated protein 1 light chain 3 -- LPS lipopolysaccharide -- PD Parkinson's disease -- STAT3 signal transducer and activator of transcription 3 -- TLR toll-like receptor -- VDR vitamin D receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116505
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Lipidation of microtubule associated protein 1 light chain 3 (LC3) is the critical step in autophagosome formation, numerous efforts have been made to design and develop small molecules that trigger LC3 lipidation to activate autophagy. In this study, we discovered a series of andrographolide derivatives as potent antagonists of vitamin D receptor (VDR) by luciferase reporter assay. Structure-activity-relationship study revealed that andrographolide derivative ZAV-12 specifically inhibited VDR signaling but not NF-κB or STAT3 activation. Western blot analysis indicates that ZAV-12 markedly triggered lipidation of LC3 in MPP + -induced Parkinsonism in vitro in an mTOR-independent manner. The ZAV-12 triggered lipidation was mediated through SREBP2 activation instead of changing expression levels of lipid synthesis genes. Furthermore, ZAV-12 treatment increased the ratio of LC3-II/LC3-I and oligomerization of A53T α-synuclein (SNCA) in SNCA triggered neurotoxicity. Taken together, these results demonstrate the therapeutic potential of VDR antagonist as novel drug candidate for neurodegenerative diseases.