Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 M Inhibitor with Pan-Coronavirus Activity.

Resulting in several million deaths globally, the COVID-19 pandemic has highlighted the criticality of antiviral drugs during a viral pandemic. Herein, we describe our efforts toward targeting SARS-CoV-2 M, a key viral protease, which led to the discovery of compound , a reversible covalent inhibitor with potent antiviral activity against several clinical variants of SARS-CoV-2. Compound demonstrated dose-dependent efficacy in a mouse-adapted SARS-CoV-2 infection model, with favorable pharmacokinetic profiles in mice, rats, dogs, and monkeys.

Entry Inhibitors of SARS-CoV-2 Targeting the Transmembrane Domain of the Spike Protein.

Despite current vaccines and therapeutics targeting SARS-CoV-2, the causative agent of the COVID-19 pandemic, cases remain high causing a burden on health care systems. Spike-protein mediated membrane fusion of SARS-CoV-2 is a critical step in viral entry. Herein, we describe entry inhibitors identified by first screening a library of about 160 compounds and then analogue synthesis.

Towards global reaction feasibility and robustness prediction with high throughput data and bayesian deep learning.

Predicting organic reaction feasibility and robustness against environmental factors is challenging. We address this issue by integrating high throughput experimentation (HTE) and Bayesian deep learning. Diverging from existing HTE studies focused on niche chemical spaces, in this work, our in-house HTE platform conducted 11,669 distinct acid amine coupling reactions in 156 working hours, yielding the most extensive single HTE dataset at a volumetric scale for industrial delivery.

Binding assays enable discovery of Tet(X) inhibitors that combat tetracycline destructase resistance.

The Tet(X) flavin-dependent monooxygenases enable tetracycline antibiotic resistance by catalysing inactivating hydroxylation, so preventing inhibition of bacterial ribosomes. Tet(X) resistance is growing rapidly, threatening the efficacy of important last-resort tetracyclines such as tigecycline. Tet(X) inhibitors have potential to protect tetracyclines in combination therapies, but their discovery has been hampered by lack of high-throughput assays.

F NMR in RNA structural biology: exploring structures, dynamics, and small molecule interactions.

RNA molecules play essential roles in numerous biological pathways, making them attractive targets for drug discovery. Despite the challenges in developing small molecules targeting RNA, the success in developing compounds that modulate RNA function underscores its therapeutic potential. F NMR spectroscopy has emerged as a powerful tool in structural biology and drug discovery, particularly for studying macromolecular structures and ligand interactions.

Structure-based discovery of novel non-covalent small molecule inhibitors of USP30.

Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30's catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors.

LRG1 inhibition promotes acute pancreatitis recovery by inducing cholecystokinin Type 1 receptor expression via Akt.

Acute pancreatitis (AP) is a common gastrointestinal disease affecting nearly 3 million people annually worldwide. Although AP is typically self-limiting, up to 20% of patients may develop life-threatening complications. Individuals who suffer from AP also have an increased likelihood of developing other exocrine and endocrine pancreatic disorders.

Therapeutic potential of targeting ubiquitin-specific proteases in colorectal cancer.

Ubiquitin-specific proteases (USPs) are a subset of deubiquitinating enzymes (DUBs) that have crucial roles in regulating key signaling pathways, DNA repair mechanisms, and immune responses by modulating the interactions and stability of proteins, including oncogenes and tumor suppressors in many cancers, such as colorectal cancer (CRC). USPs present an attractive reservoir of drug targets that could potentially overcome the shortcomings of conventional pathway-specific cancer therapies. This review explores the roles of USPs in CRC, addresses the challenges in discovering and developing USP inhibitors, highlights recent advancements in drug development, and discusses the potential of targeted protein degraders and stabilizers including proteolysis-targeting chimeras (PROTACs), molecular glues, and DUB-targeting chimeras (DUBTACs) as strategies for drugging USPs.

CAN-Scan: A multi-omic phenotype-driven precision oncology platform identifies prognostic biomarkers of therapy response for colorectal cancer.

Application of machine learning (ML) on cancer-specific pharmacogenomic datasets shows immense promise for identifying predictive response biomarkers to enable personalized treatment. We introduce CAN-Scan, a precision oncology platform, which applies ML on next-generation pharmacogenomic datasets generated from a freeze-viable biobank of patient-derived primary cell lines (PDCs). These PDCs are screened against 84 Food and Drug Administration (FDA)-approved drugs at clinically relevant doses (C), focusing on colorectal cancer (CRC) as a model system.

Fragment-Based Drug Design: From Then until Now, and Toward the Future.

Fragment-based drug design (FBDD) has emerged as a powerful strategy in drug discovery, offering a complementary approach to traditional high-throughput screening (HTS)-based drug discovery. Over almost half a century, FBDD has undergone significant evolution, leading to the discovery of multiple approved drugs in the market. The integration of structural and computational tools into FBDD has significantly enhanced its efficiency, facilitating rational drug design.

Leveraging Structural and Computational Biology for Molecular Glue Discovery.

The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin-proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues.

Perspectives on Applications of F-NMR in Fragment-Based Drug Discovery.

Fragment-based drug discovery is a powerful approach in drug discovery, applicable to a wide range of targets. This method enables the discovery of potent compounds that can modulate target functions, starting from fragment compounds that bind weakly to the targets. While biochemical, biophysical, and cell-based assays are commonly used to identify fragments, F-NMR spectroscopy has emerged as a powerful tool for exploring interactions between biomolecules and ligands.

H, N and C backbone resonance assignment of the N-terminal region of Zika virus NS4B protein in detergent micelles.

Zika virus has raised global concerns due to its link to microcephaly and Guillain-Barré syndrome in adults. One of viral nonstructural proteins-NS4B, an integral membrane protein, plays crucial roles in viral replication by interacting with both viral and host proteins, rendering it an attractive drug target for antiviral development. We purified the N-terminal region of ZIKV NS4B (NS4B NTD) and reconstituted it into detergent micelles.

Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads.

Current Status of Computational Approaches for Small Molecule Drug Discovery.

2024 has been an exciting year for computational sciences, with the Nobel Prize in Physics awarded for "artificial neural network" and the Nobel Prize in Chemistry presented for "protein structure prediction and design". Given the rapid advancements in Computer-Aided Drug Design (CADD) and Artificial Intelligence in Drug Discovery (AIDD), a document summarizing their current standing and future directions would be timely and relevant to the readership of . This piece of commentary aims to highlight recent developments, key challenges, and potential synergies between these fields, contributing to ongoing discussions in the literature and scientific blogs.

A novel three-part pharynx and its parallel evolution within symbiotic marine nematodes (Desmodoroidea, Stilbonematinae).

Stilbonematinae are nematodes commonly found in shallow marine sands. They are overgrown by a genus- and species-specific coat of chemoautotrophic sulphur-oxidizing ectosymbiotic bacteria which profit from the vertical migration of their hosts through the chemocline by alternately gaining access to oxidizing and reducing chemical species, while in return, the host feeds on its symbionts. The subfamily exhibits a large morphological variability; e.

Protocol to perform fragment screening using NMR spectroscopy.

Fragment-based drug design plays an important role in drug discovery. Protein-observed NMR experiments with isotopically labeled samples are used to probe target-ligand interactions and map the ligand-binding sites. Here, we present a protocol to perform fragment screening using NMR spectroscopy.

Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless.

Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-addicted cancers. An integral membrane protein known as Wntless (WLS/Evi) is essential for Wnt secretion.

A high-throughput cell-based screening method for Zika virus protease inhibitor discovery.

Zika virus (ZIKV) continues to pose a significant global public health threat, with recurring regional outbreaks and potential for pandemic spread. Despite often being asymptomatic, ZIKV infections can have severe consequences, including neurological disorders and congenital abnormalities. Unfortunately, there are currently no approved vaccines or antiviral drugs for the prevention or treatment of ZIKV.

Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D-Cys6-LHRH vedotin, against ovarian cancer cell lines.

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017.

Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity.

Background & Aims: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC.

Identification of small-molecule binding sites of a ubiquitin-conjugating enzyme-UBE2T through fragment-based screening.

UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using F-nuclear magnetic resonance (NMR) and validated the hits with H- N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies.

GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876.

New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target.

Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer.

UBE2T is an E2 ubiquitin ligase critical for ubiquitination of substrate and plays important roles in many diseases. Despite the important function, UBE2T is considered as an undruggable target due to lack of a pocket for binding to small molecules with satisfied properties for clinical applications. To develop potent and specific UBE2T inhibitors, we adopted a high-throughput screening assay and two compounds-ETC-6152 and ETC-9004 containing a sulfone tetrazole scaffold were identified.