Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors.

The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CL, Nsp5) and the papain-like protease (PL) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of , a nonpeptide 3CL inhibitor with an IC of 0.

Assessing Genetic Diversity in Endangered Plant : Chloroplast Genome Assembly and Simple Sequence Repeat Marker-Based Evaluation.

T. L. Wu, an endemic species in China, is listed as a key protected wild plant in Guangdong Province.

Role of anthocyanin metabolic diversity in bract coloration of Curcuma alismatifolia varieties.

Anthocyanins are one of the key metabolites influencing the coloration of ornamental bracts in plants. Curcuma alismatifolia is an emerging ornamental plant, known for the rich diversity in the coloration of its bracts and the variety of anthocyanins present. However, the specific anthocyanin metabolites contributing to this diversity are not entirely clear.

PPIA dictates NRF2 stability to promote lung cancer progression.

Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability.

Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model.

Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4--dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from with moderate potency against PDE4 (IC = 3.26 ± 0.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.

Pigment Diversity in Leaves of × Birdsey and Transcriptomic and Metabolic Comparisons between Red and White Leaves.

Leaf color is a key ornamental characteristic of cultivated caladium ( × Birdsey), a plant with diverse leaf colors. However, the genetic improvement of leaf color in cultivated caladium is hindered by the limited understanding of leaf color diversity and regulation. In this study, the chlorophyll and anthocyanin content of 137 germplasm resources were measured to explore the diversity and mechanism of leaf color formation in cultivated caladium.

Ent-labdane-type diterpene glycosides obtained from Rubus chingii Hu and their inhibitory effects on PDE5A activity.

In this study, 16 new ent-labdane-type diterpene glycosides, designated as goshonosides J1-J16 (1-16), along with nine previously known diterpene glycosides (17-25) were extracted from the fruits of Rubus chingii Hu. The structures of goshonosides J1-J16 were elucidated using various analytical techniques, such as nuclear magnetic resonance, electron capture detector ECD, high-resolution electrospray ionization mass spectrometry HREIMS, single-crystal X-ray diffraction, and hydrolysis. Furthermore, the isolates' efficacy in inhibiting the activity of phosphodiesterase type 5 A was evaluated.

Design, synthesis and biological evaluation of betulinic acid derivatives as potential inhibitors of 3CL-protease of SARS-CoV-2.

During the coronavirus reproduction process, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are accountable for the fragmentation of two polyprotein precursors (pp1a/pp1ab) into substructural proteins. These two proteins are vital for the replication and transcription of the viral genome. Therefore, 3CLpro is a key protein and target for the design of coronavirus inhibitors.

Repurposing of Rutan showed effective treatment for COVID-19 disease.

Unlabelled: Previously, from the tannic sumac plant (), we developed the Rutan 25 mg oral drug tablets with antiviral activity against influenza A and B viruses, adenoviruses, paramyxoviruses, herpes virus, and cytomegalovirus. Here, our re-purposing study demonstrated that Rutan at 25, 50, and 100 mg/kg provided a very effective and safe treatment for COVID-19 infection, simultaneously inhibiting two vital enzyme systems of the SARS-CoV-2 virus: 3C-like proteinase (3CLpro) and RNA-dependent RNA polymerase (RdRp). There was no drug accumulation in experimental animals' organs and tissues.

Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3.

Fatty-acid binding protein 4 (FABP4) presents an attractive target for therapeutic intervention in metabolic and inflammatory diseases in recent years. However, highly similar three-dimensional structures and fatty acid binding ability of multiple FABP family members pose a significant challenge in design of FABP4-selective inhibitors. Particularly, inhibition of FABP3 raises safety concerns such as cardiac dysfunction and exercise intolerance.

Multi-omics for COVID-19: driving development of therapeutics and vaccines.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 has raised global concern for public health and economy. The development of therapeutics and vaccines to combat this virus is continuously progressing. Multi-omics approaches, including genomics, transcriptomics, proteomics, metabolomics, epigenomics and metallomics, have helped understand the structural and molecular features of the virus, thereby assisting in the design of potential therapeutics and accelerating vaccine development for COVID-19.

Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC values ranging from 0.

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature.

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.

Discovery of novel cGAS inhibitors based on natural flavonoids.

Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases.

Cross-Compatibility in Interspecific Hybridization of Different Accessions.

is extensively cultivated as a medicinal and ornamental plant in tropical and subtropical regions. Due to the bright bract color, distinctive inflorescence and long blooming period, it has become a new favorite in terms of the urban landscape, potted flowers and cut flowers. However, little research on breeding new cultivars using traditional plant breeding methods is available on the genus .

Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group.

3CL is an attractive target for the treatment of COVID-19. Using the scaffold hopping strategy, we identified a potent inhibitor of 3CL () that contains a thiocyanate moiety as a novel warhead that can form a covalent bond with Cys145 of the protein. Tandem mass spectrometry (MS/MS) and X-ray crystallography confirmed the mechanism of covalent formation between and the protein in its catalytic pocket.

Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial.

Background: SIM0417 (SSD8432) is an orally administered coronavirus main proteinase (3CL) inhibitor with potential anti-SARS-CoV-2 activity. This study aimed to evaluate the efficacy and safety of SIM0417 plus ritonavir (a pharmacokinetic enhancer) in adults with COVID-19.

Methods: This was a randomised, double-blind, placebo-controlled, phase 1b study in China.

Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.

Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations.

Discovery of Polyphenolic Natural Products as SARS-CoV-2 M Inhibitors for COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods.