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Essays Biochem ; 65(6): 847-856, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1537347


Nuclear receptors are classically defined as ligand-activated transcription factors that regulate key functions in reproduction, development, and physiology. Humans have 48 nuclear receptors, which when dysregulated are often linked to diseases. Because most nuclear receptors can be selectively activated or inactivated by small molecules, they are prominent therapeutic targets. The basic understanding of this family of transcription factors was accelerated in the 1980s upon the cloning of the first hormone receptors. During the next 20 years, a deep understanding of hormone signaling was achieved that has translated to numerous clinical applications, such as the development of standard-of-care endocrine therapies for hormonally driven breast and prostate cancers. A 2004 issue of this journal reviewed progress on elucidating the structures of nuclear receptors and their mechanisms of action. In the current issue, we focus on the broad application of new knowledge in this field for therapy across diverse disease states including cancer, cardiovascular disease, various inflammatory diseases, the aging brain, and COVID-19.

Receptors, Cytoplasmic and Nuclear/pharmacology , Receptors, Cytoplasmic and Nuclear/therapeutic use , Animals , COVID-19/drug therapy , Cardiovascular Diseases/drug therapy , Female , Humans , Inflammation/drug therapy , Male , Neoplasms/drug therapy , Receptors, Cytoplasmic and Nuclear/metabolism , SARS-CoV-2 , Signal Transduction , Transcription Factors/metabolism
Cells ; 10(3)2021 03 05.
Article in English | MEDLINE | ID: covidwho-1129686


The superfamily of nuclear receptors (NRs), composed of ligand-activated transcription factors, is responsible for gene expression as a reaction to physiological and environmental changes. Transcriptional machinery may require phase separation to fulfil its role. Although NRs have a similar canonical structure, their C-terminal domains (F domains) are considered the least conserved and known regions. This article focuses on the peculiar molecular properties of the intrinsically disordered F domain of the ecdysteroid receptor from the Aedes aegypti mosquito (AaFEcR), the vector of the world's most devastating human diseases such as dengue and Zika. The His-Pro-rich segment of AaFEcR was recently shown to form the unique poly-proline helix II (PPII) in the presence of Cu2+. Here, using widefield microscopy of fluorescently labeled AaFEcR, Zn2+- and Cu2+-induced liquid-liquid phase separation (LLPS) was observed for the first time for the members of NRs. The perspectives of this finding on future research on the F domain are discussed, especially in relation to other NR members.

Ions/metabolism , Mosquito Vectors/pathogenicity , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Aedes , Animals , Humans
Drug Discov Today ; 25(10): 1775-1781, 2020 10.
Article in English | MEDLINE | ID: covidwho-611872


Coronavirus 2019 (COVID-19; caused by Severe Acute Respiratory Syndrome Coronavirus 2; SARS-CoV-2) is a currently global health problem. Previous studies showed that blocking nucleocytoplasmic transport with exportin 1 (XPO1) inhibitors originally developed as anticancer drugs can quarantine key viral accessory proteins and genomic materials in the nucleus of host cell and reduce virus replication and immunopathogenicity. These observations support the concept of the inhibition of nuclear export as an effective strategy against an array of viruses, including influenza A, B, and SARS-CoV. Clinical studies using the XPO1 inhibitor selinexor as a therapy for COVID-19 infection are in progress.

Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cell Nucleus/drug effects , Drug Design , Karyopherins/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , SARS-CoV-2/pathogenicity , Active Transport, Cell Nucleus , Animals , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cell Nucleus/immunology , Cell Nucleus/metabolism , Cell Nucleus/virology , Host-Pathogen Interactions , Humans , Karyopherins/metabolism , Molecular Targeted Therapy , Receptors, Cytoplasmic and Nuclear/metabolism , SARS-CoV-2/immunology