Expression of Human Nuclear Receptors in Plants for the Discovery of Plant-Derived Ligands

Abstract

Plants have the potential to produce a wide array of secondary metabolites that have utility as drugs to treat human diseases. To tap this potential, functional human nuclear receptors have been expressed in plants to create in planta screening assays as a tool to discover natural product ligands. Assays have been designed and validated using 3 nuclear receptors: the estrogen receptor (ER), the androgen receptor (AR), and the heterodimeric retinoid X receptor-α plus thyroid hormone receptor-β (RXRA/THRB). Nuclear receptor-reporter constructs have been expressed in plants to detect the presence of natural ligands that are produced de novo in several plant species during different stages of development, in various tissues, and in response to different stress elicitors. Screening experiments with ER, AR, and RXRA/THRB have been conducted, leading to the identification of plant sources of natural product ligands of human nuclear receptors. This in planta screen has led to the identification of previously unreported ER ligands, providing evidence of the complementary value of this approach to current in vitro high-throughput screening assays. (Journal of Biomolecular Screening 2007:385-395)

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

“…These may be metabolites that are present in the wild-type plant or, if a mutation alters a relevant biosynthetic pathway, then “novel” active metabolites with enhanced activity at the target may be generated (Rogers et al 2003). Target proteins have previously been expressed in plant cells as screens (Littleton 2007, Doukhanina et al 2007, Zhao et al 2012, Gunjan et al 2013), but this is the first report in which survival of mutant plant cells expressing a foreign target protein has been used to direct secondary metabolism toward a specific pharmacological phenotype. Proof of concept uses Lobelia cardinalis , which contains lobinaline, a novel inhibitor of the human dopamine transporter (DAT) (Littleton et al 2004, Brown et al 2016).…”