1α,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis

Zongtao Lin (1) , Hao Chen (1) , Anna Belorusova (2) , John Bollinger , Edith Tang (3) , Zorica Janjetovic (4) , Tae-Kang Kim (4) , Zhongzhi Wu (1) , Duane Miller (1) , Andrzef Slominski (4) , Arnold Postlethwaite (1) , Robert Tuckey (3) , Natacha Rochel-Guiberteau (5) , Wei Li (1)

1 UTHSC - The University of Tennessee Health Science Center [Memphis]
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 UWA - The University of Western Australia
4 UAB - University of Alabama at Birmingham [ Birmingham]
5 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.

Domaines: Chimie thérapeutique; Cristallographie; Biologie structurale [q-bio.BM]

Zongtao Lin, Hao Chen, Anna Belorusova, John Bollinger, Edith Tang, et al.. 1α,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis. Scientific Reports, 2017, 7 (1), pp.10193. ⟨10.1038/s41598-017-10917-7⟩. ⟨hal-03676420⟩