Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.

SPMs exert anti-inflammatory and pro-resolving effects through positive allosteric modulation of the prostaglandin EP4 receptor.

Inflammation is a protective response to pathogens and injury. To be effective it needs to be resolved by endogenous mechanisms in order to avoid prolonged and excessive inflammation, which can become chronic. Specialized pro-resolving mediators (SPMs) are a group of lipids derived from omega-3 fatty acids, which can induce the resolution of inflammation.

Bidirectional Effect of Long-Term Δ-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome.

Brain aging is associated with cognitive decline, reduced synaptic plasticity, and altered metabolism. The activity of mechanistic target of rapamycin (mTOR) has a major impact on aging by regulating cellular metabolism. Although reduced mTOR signaling has a general antiaging effect, it can negatively affect the aging brain by reducing synaptogenesis and thus cognitive functions.

Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy.

The cyclodepsipeptide FR900359 (FR) and its analogs are able to selectively inhibit the class of G proteins by blocking GDP/GTP exchange. The inhibitor binding site of G has been characterized by X-ray crystallography, and various binding and functional studies have determined binding kinetics and mode of inhibition. Here we investigate isotope-labeled FR bound to the membrane-anchored G protein heterotrimer by solid-state nuclear magnetic resonance (ssNMR) and in solution by liquid-state NMR.

Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity.

SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (M). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety.

Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough.

High levels of soluble CD73 unveil resistance to BRAF inhibitors in melanoma cells.

Melanoma cells express high levels of CD73 that produce extracellular immunosuppressive adenosine. Changes in the CD73 expression occur in response to tumor environmental factors, contributing to tumor phenotype plasticity and therapeutic resistance. Previously, we have observed that CD73 expression can be up-regulated on the surface of melanoma cells in response to nutritional stress.

Potent, Selective Agonists for the Cannabinoid-like Orphan G Protein-Coupled Receptor GPR18: A Promising Drug Target for Cancer and Immunity.

The human orphan G protein-coupled receptor GPR18, activated by Δ-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in β-arrestin recruitment assays.

Development of an active-site titrant for SARS-CoV-2 main protease as an indispensable tool for evaluating enzyme kinetics.

A titrant for the SARS-CoV-2 main protease (M) was developed that enables, for the first time, the exact determination of the concentration of the enzymatically active M by active-site titration. The covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme-titrant complex. Four fluorogenic substrates of M, including a prototypical, internally quenched Dabcyl-EDANS peptide, were compared in terms of solubility under typical assay conditions.

Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist.

P2X4 receptors are ATP-gated cation channels that were proposed as novel drug targets due to their role in inflammation and neuropathic pain. Only few potent and selective P2X4 receptor antagonists have been described to date. Labeled tool compounds suitable for P2X4 receptor binding studies are lacking.

Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs.

Given the crucial role of the main protease (M) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M. Our systematic approach combined an M active-site scanning by combinatorially assembled azanitriles with structure-based design.

Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A Receptor.

The adenosine A receptor (AAR) belongs to the rhodopsin-like G protein-coupled receptor (GPCR) family, which constitutes the largest class of GPCRs. Partial agonists show reduced efficacy as compared to physiological agonists and can even act as antagonists in the presence of a full agonist. Here, we determined an X-ray crystal structure of the partial AAR agonist 2-amino-6-[(1-imidazol-2-ylmethyl)sulfanyl]-4--hydroxyphenyl-3,5-pyridinedicarbonitrile (LUF5834) in complex with the AAR construct A-PSB2-bRIL, stabilized in its inactive conformation and being devoid of any mutations in the ligand binding pocket.

Detection of Active SARS-CoV-2 3CL Protease in Infected Cells Using Activity-Based Probes with a 2,6-Dichlorobenzoyloxymethyl Ketone Reactive Warhead.

The 3CL protease (3CLpro) is a viral cysteine protease of SARS-CoV-2 and is responsible for the main processing of the viral polyproteins involved in viral replication and proliferation. Despite the importance of 3CLpro as a drug target, the intracellular dynamics of active 3CLpro, including its expression and subcellular localization in SARS-CoV-2-infected cells, are poorly understood. Herein, we report an activity-based probe (ABP) with a clickable alkyne and an irreversible warhead for the SARS-CoV-2 3CL protease.

Correction to "Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity".

[This corrects the article DOI: 10.1021/acsptsci.3c00313.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists.

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity.

Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained.

Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2.

Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation.

Suberin, the hallmark constituent of bark, identified in a 45-million-year-old monkeyhair tree (Coumoxylon hartigii) from Geiseltal, Germany.

Suberin, a complex biopolymer, forms a water- and gas-insoluble barrier that protects the inner tissues of plants. It is abundant in tree bark, particularly in the cork oak Quercus suber. Anatomically, fossil bark has been described since the Devonian.