Abnormal Cannabidiol Modulates Vitamin A Metabolism by Acting as a Competitive Inhibitor of CRBP1

Silvaroli, Josie A.; Widjaja-Adhi, Made K.; Trischman, Thomas; Chelstowska, Sylwia; Horwitz, Samantha; Banerjee, Surajit; Kiser, Philip D.; Blaner, William S.; Golczak, Marcin

doi:10.1021/acschembio.8b01070

Title: Abnormal Cannabidiol Modulates Vitamin A Metabolism by Acting as a Competitive Inhibitor of CRBP1

Journal Article · 05 February 2019 · ACS Chemical Biology

DOI: https://doi.org/10.1021/acschembio.8b01070 · OSTI ID:1515286

Silvaroli, Josie A. ^[1]; Widjaja-Adhi, Made K. ^[1]; Trischman, Thomas ^[1]; Chelstowska, Sylwia ^[1]; Horwitz, Samantha ^[2]; Banerjee, Surajit ^[3];

^[4]; Blaner, William S. ^[5];

^[6]

Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine
Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine; Kent State Univ., Kent, OH (United States)
Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine and Cleveland Center for Membrane and Structural Biology; Louis Stokes Cleveland VA Medical Center, Cleveland, OH (United States)
Columbia Univ., New York, NY (United States). College of Physicians and Surgeons
Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine and Cleveland Center for Membrane and Structural Biology

Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Here in this paper we identify abnormal cannabidiol (abn-CBD) as a nonretinoid inhibitor of cellular retinol-binding protein 1 (CRBP1). X-ray crystal structures of CRBP1 in complex with abn-CBD and its derivatives revealed a distinctive mode of protein–ligand interaction and provided a molecular basis for the high affinity and selectivity of this compound. We demonstrated that abn-CBD modulates the flux of retinoids via the retinoid cycle in vivo. Furthermore, the biological activity of abn-CBD was evidenced by its ability to protect against light-induced retinal damage in Balb/cJ mice. Altogether, our findings indicate that targeting selected CRBPs with a small-molecule inhibitor can potentially lead to the development of new therapeutic agents to counteract diseases with etiologies involving imbalance in retinoid metabolism or signaling.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS); Department of Veterans Affairs

Grant/Contract Number:: AC02-06CH11357; AC02-76SF00515

OSTI ID:: 1515286

Journal Information:: ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 3 Vol. 14; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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