Sub-stoichiometric Modulation of Viral Targets-Potent Antiviral Agents That Exploit Target Vulnerability.

The modulation of oligomeric viral targets at sub-stoichiometric ratios of drug to target has been advocated for its efficacy and potency, but there are only a limited number of documented examples. In this Viewpoint, we summarize the invention of the HIV-1 maturation inhibitor fipravirimat and discuss the emerging details around the mode of action of this class of drug that reflects inhibition of a protein composed of 1,300-1,600 monomers that interact in a cooperative fashion. Similarly, the HCV NS5A inhibitor daclatasvir has been shown to act in a highly sub-stoichiometric fashion, inhibiting viral replication at concentrations that are ∼23,500 lower than that of the protein target.

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data.

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without knowledge, will vastly enhance the understanding of microorganisms' role in ecology and human health.

Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly.

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is β, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold.

The pyridazine heterocycle in molecular recognition and drug discovery.

The pyridazine ring is endowed with unique physicochemical properties, characterized by weak basicity, a high dipole moment that subtends π-π stacking interactions and robust, dual hydrogen-bonding capacity that can be of importance in drug-target interactions. These properties contribute to unique applications in molecular recognition while the inherent polarity, low cytochrome P450 inhibitory effects and potential to reduce interaction of a molecule with the cardiac hERG potassium channel add additional value in drug discovery and development. The recent approvals of the gonadotropin-releasing hormone receptor antagonist relugolix () and the allosteric tyrosine kinase 2 inhibitor deucravacitinib () represent the first examples of FDA-approved drugs that incorporate a pyridazine ring.

Persistently Elevated HBV Viral-Host Junction DNA in Urine as a Biomarker for Hepatocellular Carcinoma Minimum Residual Disease and Recurrence: A Pilot Study.

Hepatitis B virus (HBV)-host junction sequences (HBV-JSs) has been detected in the urine of patients with HBV infection. This study evaluated HBV-JSs as a marker of minimum residual disease (MRD) and tumor recurrence after treatment in HBV-hepatocellular carcinoma (HCC) patients. Archived serial urine DNA from two HBV-HCC with recurrence as confirmed by MRI and four HBV-related cirrhosis (LC) patients were used.

Opportunities to address gaps in early detection and improve outcomes of liver cancer.

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates.

Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling.

Malignant breast cancer (BC) remains incurable mainly due to the cancer cell metastasis, which is mostly related to the status of Estrogen receptor alpha (ERα). However, our understanding of the mechanisms through which ERα regulates cancer cell metastasis remains limited. Here we identified a miR-29a-PTEN-AKT axis as a downstream signaling pathway of ERα governing breast cancer progression and metastasis.

Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties.

The mode of action by which the orphan drug anagrelide (), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood. Recent studies indicate that stabilizes a complex between PDE3A and Schlafen 12, protecting it from degradation while activating its RNase activity.

Applications of Bioisosteres in the Design of Biologically Active Compounds.

The design of bioisosteres represents a creative and productive approach to improve a molecule, including by enhancing potency, addressing pharmacokinetic challenges, reducing off-target liabilities, and productively modulating physicochemical properties. Bioisosterism is a principle exploited in the design of bioactive compounds of interest to both medicinal and agricultural chemists, and in this review, we provide a synopsis of applications where this kind of molecular editing has proved to be advantageous in molecule optimization. The examples selected for discussion focus on bioisosteres of carboxylic acids, applications of fluorine and fluorinated motifs in compound design, some applications of the sulfoximine functionality, the design of bioisosteres of drug-HO complexes, and the design of bioisosteres of the phenyl ring.

Circulating Biomarkers for the Early Diagnosis and Management of Hepatocellular Carcinoma with Potential Application in Resource-Limited Settings.

Hepatocellular carcinoma (HCC) is among the world's third most lethal cancers. In resource-limited settings (RLS), up to 70% of HCCs are diagnosed with limited curative treatments at an advanced symptomatic stage. Even when HCC is detected early and resection surgery is offered, the post-operative recurrence rate after resection exceeds 70% in five years, of which about 50% occur within two years of surgery.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, gene deletion within the 13q21.

Emerging heterologous mRNA-based booster strategies within the COVID-19 vaccine landscape.

Messenger RNA (mRNA)-based vaccine platforms used for the development of mRNA-1273 and BNT162b2 have provided a robust adaptable approach to offer protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, as variants of concern (VoCs), such as omicron and associated sub-variants, emerge, boosting strategies must also adapt to keep pace with the changing landscape. Heterologous vaccination regimens involving the administration of booster vaccines different than the primary vaccination series offer a practical, effective, and safe approach to continue to reduce the global burden of coronavirus disease 2019 (COVID-19).

Circulating messenger RNA variants as a potential biomarker for surveillance of hepatocellular carcinoma.

Background And Rationale: Liver derived messenger ribonucleic acid (mRNA) transcripts were reported to be elevated in the circulation of hepatocellular carcinoma (HCC) patients. We now report the detection of high-risk mRNA variants exclusively in the circulation of HCC patients. Numerous genomic alleles such as single nucleotide polymorphisms (SNPs), nucleotide insertions and deletions (called Indels), splicing variants in many genes, have been associated with elevated risk of cancer.

Heat Shock Protein Family A Member 1 Promotes Intracellular Amplification of Hepatitis B Virus Covalently Closed Circular DNA.

Hepatitis B virus (HBV) contains a partially double-stranded relaxed circular DNA (rcDNA) genome that is converted into a covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocyte by cellular DNA repair machinery. cccDNA associates with nucleosomes to form a minichromosome that transcribes RNA to support the expression of viral proteins and reverse transcriptional replication of viral DNA. In addition to the synthesis from incoming virion rcDNA, cccDNA can also be synthesized from rcDNA in the progeny nucleocapsids within the cytoplasm of infected hepatocytes via the intracellular amplification pathway.

Acetylation of nuclear receptors in health and disease: an update.

Lysine acetylation is a common reversible post-translational modification of proteins that plays a key role in regulating gene expression. Nuclear receptors (NRs) include ligand-inducible transcription factors and orphan receptors for which the ligand is undetermined, which together regulate the expression of genes involved in development, metabolism, homeostasis, reproduction and human diseases including cancer. Since the original finding that the ERα, AR and HNF4 are acetylated, we now understand that the vast majority of NRs are acetylated and that this modification has profound effects on NR function.

Pregenomic RNA Launch Hepatitis B Virus Replication System Facilitates the Mechanistic Study of Antiviral Agents and Drug-Resistant Variants on Covalently Closed Circular DNA Synthesis.

Hepatitis B virus (HBV) replicates its genomic DNA by reverse transcription of an RNA intermediate, termed pregenomic RNA (pgRNA), within nucleocapsid. It had been shown that transfection of -transcribed pgRNA initiated viral replication in human hepatoma cells. We demonstrated here that viral capsids, single-stranded DNA, relaxed circular DNA (rcDNA) and covalently closed circular DNA (cccDNA) became detectable sequentially at 3, 6, 12, and 24 h post-pgRNA transfection into Huh7.

The Marine Compound Tartrolon E Targets the Asexual and Early Sexual Stages of .

New therapeutic agents for cryptosporidiosis are a critical medical need. The marine organic compound, tartrolon E (trtE), is highly effective against multiple apicomplexan parasites, including . Understanding the mechanism of action of trtE is required to advance in the drug development pipeline.

The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.

Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook.

Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies.

Assays for the Spectrum of Circulating Tumor Cells.

Cancer cells sharing stem cell properties are called "cancer stem cells" (CSCs). CSCs have distinct metabolic properties, are intrinsically drug resistant evading chemotherapies, are regulated by miRNA networks and participate in tumor relapse and metastases. During metastatic dissemination, circulating tumor cells (CTCs) invade distant organs and settle in supportive niches.

A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response.

Flavivirus infection of cells induces massive rearrangements of the endoplasmic reticulum (ER) membrane to form viral replication organelles (ROs) which segregates viral RNA replication intermediates from the cytoplasmic RNA sensors. Among other viral nonstructural (NS) proteins, available evidence suggests for a prominent role of NS4B, an ER membrane protein with multiple transmembrane domains, in the formation of ROs and the evasion of the innate immune response. We previously reported a benzodiazepine compound, BDAA, which specifically inhibited yellow fever virus (YFV) replication in cultured cells and in vivo in hamsters, with resistant mutation mapped to P219 of NS4B protein.

Urine DNA biomarkers for hepatocellular carcinoma screening.

Background: Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test.

Methods: Candidate markers in urine were selected from HCC and controls.