Synthesis and characterization of targeted 17β-hydroxysteroid dehydrogenase type 7 inhibitors.

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer.

Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations.

SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using QPLD, pseudovirus ACE2 Inhibition -Time Resolved Forster/Fluorescence energy transfer (TR-FRET) Assay Screening, and Molecular Dynamics simulations (MDS).

Search of Novel Small Molecule Inhibitors for the Main Protease of SARS-CoV-2.

The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex.

CRIF1-CDK2 Interface Inhibitors Enhance Taxol Inhibition of the Lethal Triple-Negative Breast Cancer.

Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2).

An unprecedented endocrine target for ovarian cancer: inhibiting 17β-HSD7 supresses cancer cell proliferation and arrests G2/M cycle.

Epithelial ovarian cancer, widely suggested as endocrine-related cancer, yields a low survival rate among patients. Despite intensive research for nearly a century, there have been no fundamental advances in treatment. The reductive 17β-HSD7 is a special enzyme possessing a remarkable dual activity in both the biosynthesis of the most potent estrogen estradiol and the inactivation of the most active androgen dihydrotestosterone.

The multi-specific human 17 beta-hydroxysteroid dehydrogenase type 7: Non-competitive inhibitors can target different catalyses to facilitate breast cancer treatment.

Human 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a special multifunctional enzyme, activates the estrogen estrone while inactivating the potent androgen dihydrotestosterone. Thus, this enzyme has become an ideal target for hormone-dependent breast cancer treatment, as its inhibition leads to estradiol reduction and dihydrotestosterone restoration. However, a particular concern has arisen related to an additional role in cholesterol biosynthesis, as inhibition of the enzyme may lead to undesirable side effects.

Human endeavor for anti-SARS-CoV-2 pharmacotherapy: A major strategy to fight the pandemic.

The global spread of COVID-19 constitutes the most dangerous pandemic to emerge during the last one hundred years. About seventy-nine million infections and more than 1.7 million death have been reported to date, along with destruction of the global economy.

Memory-based optical polarization conversion in a double-[Formula: see text] atomic system with degenerate Zeeman states.

Optical memory based on the electromagnetically induced transparency (EIT) in a double-[Formula: see text] atomic system provides a convenient way to convert the frequency, bandwidth or polarization of an optical pulse by storing it in one [Formula: see text] channel and retrieving it from another. This memory-based optical converter can be used to bridge the quantum nodes which have different physical properties in a quantum network. However, in real atoms, each energy level usually contains degenerate Zeeman states, which may lead to additional energy loss, as has been discussed in our recent theoretical paper (Tsai et al.

Novel Coronavirus Polymerase and Nucleotidyl-Transferase Structures: Potential to Target New Outbreaks.

The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.

Meta-Analysis of steroid-converting enzymes and related receptors in prostate cancer suggesting novel combined therapies.

Androgen receptor (AR) signaling is essential for prostate cancer (PC) progression and treatment. Experiments have demonstrated that the intratumoral androgen levels are not affected by circulating androgen levels, but rather modulated by local steroid-converting enzyme activities. The expression modulation status of human steroid-converting enzymes and nuclear receptors are of great promise to identify novel therapeutic targets.

Steroid enzyme and receptor expression and regulations in breast tumor samples - A statistical evaluation of public data.

In spite of the significant progress of estrogen-dependent breast cancer (BC) treatment, aromatase inhibitor resistance is a major problem limiting the clinical benefit of this frontier endocrine-therapy. The aim of this study was to determine the differential expression of steroid-converting enzymes between tumor and adjacent normal tissues, as well as their correlation in modulating intratumoral steroid-hormone levels in post-menopausal estrogen-dependent BC. RNA sequencing dataset (n = 1097) of The-Cancer-Genome-Atlas (Breast Invasive Carcinoma) retrieved through the data portal of Genomic Data Commons was used for differential expressions and expression correlation analyses by Mann-Whitney U and Spearman's rank test, respectively.

Transcriptome of 17β-hydroxysteroid dehydrogenase type 2 plays both hormone-dependent and hormone-independent roles in MCF-7 breast cancer cells.

Breast cancer is a major cause of cancer-related death for women in western countries. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) play important roles in the last step of sex-hormone activation and the first step of sex-hormone inactivation. 17β-HSD2 is responsible for oxidizing the sex hormones.

Mutual regulations and breast cancer cell control by steroidogenic enzymes: Dual sex-hormone receptor modulation upon 17β-HSD7 inhibition.

Reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) play crucial roles in respectively regulating steroids and glucocorticoids for the progression of hormone-dependent breast cancer. Most studies focused on the function and individual regulation of these enzymes. However, mutual regulation of these enzymes and the induced modulation on the estrogen and androgen receptors for breast cancer promotion are not yet clear.

siRNA-based breast cancer therapy by suppressing 17β-hydroxysteroid dehydrogenase type 1 in an optimized xenograft cell and molecular biology model in vivo.

Purpose: Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17β-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity.

Crystal structures of human 17β-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP reveal the mechanism of substrate inhibition.

Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17β-HSD members, 17β-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β-HSD1 in complex with estrone (E1) and cofactor analog NADP , demonstrating critical enzyme-substrate-cofactor interactions.

CRIF1-CDK2 Interface Inhibitors: An Unprecedented Strategy for Modulation of Cell Radiosensitivity.

Cyclin-dependent kinases (CDKs) are historic therapeutic targets implicated in tumorigenic events due to their critical involvement in the cell cycle phase. However, selectivity has proven to be a bottleneck, causing repeated failures. Previously, we reported CR6-interacting factor 1 (CRIF1), acting as a cell cycle negative regulator through interaction with CDK2.

The dual sex hormone specificity for human reductive 17β-hydroxysteroid dehydrogenase type 7: Synergistic function in estrogen and androgen control.

Human 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 and 7 catalyze the final step of estrogen activation and the first step in androgen inactivation. It has been shown in breast cancer cells that DHT has a suppression effect on cell proliferation, counteracting the estrogen growth effect. However, the exact kinetic function of 17β-HSD7 in steroidogenesis was not determined.

Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays a pivotal role in the progression of estrogen-related diseases because of its involvement in the biosynthesis of estradiol (E2), constituting a valuable therapeutic target for endocrine treatment. In the present study, we successfully cocrystallized the enzyme with the reversible inhibitor 2-methoxy-16β-( m-carbamoylbenzyl)-E2 (2-MeO-CC-156) as well as the enzyme with the irreversible inhibitor 3-(2-bromoethyl)-16β-( m-carbamoylbenzyl)-17β-hydroxy-1,3,5(10)-estratriene (PBRM). The structures of ternary complexes of 17β-HSD1-2-MeO-CC-156-NADP and 17β-HSD1-PBRM-NADP comparatively show the formation of a covalent bond between His and the bromoethyl side chain of the inhibitor in the PBRM structure.

Steroid sulfatase inhibition success and limitation in breast cancer clinical assays: An underlying mechanism.

Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant.

Highly Efficient Coherent Optical Memory Based on Electromagnetically Induced Transparency.

Quantum memory is an important component in the long-distance quantum communication based on the quantum repeater protocol. To outperform the direct transmission of photons with quantum repeaters, it is crucial to develop quantum memories with high fidelity, high efficiency and a long storage time. Here, we achieve a storage efficiency of 92.