The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 plays a pivotal role in the life cycle of the novel coronavirus and stands as a significant and promising target for anti-SARS-CoV-2 drugs. Non-nucleoside inhibitors (NNIs), as a category of compounds directed against SARS-CoV-2 RdRp, exhibit a unique and highly effective mechanism, effectively overcoming various factors contributing to drug resistance against nucleoside inhibitors (NIs). This review investigates various NNIs, including both natural and synthetic inhibitors, that closely interacting with the SARS-CoV-2 RdRp with valid evidences from in vitro and in silico studies.

Synthetic inhibitors and organic amendment have been proposed for mitigating greenhouse gas N2O emissions. However, their combined effect on the N2O emissions and ammonia-oxidizer (ammonia-oxidizing bacteria and archaea, AOB and AOA) communities remains unclear in calcareous soils under climate warming. We conducted two incubation experiments (25 and 35 °C) to examine how N2O emissions and AOA and AOB communities responded to organic amendment (urea plus cattle manure, UCM), and in combination with urease (N-(n-butyl) thiophosphoric triamide, NBPT) and nitrification inhibitor (nitrapyrin). The treatments of UCM + nitrapyrin and UCM + nitrapyrin + NBPT significantly lowered total N2O emissions by average 64.5 and 71.05% at 25 and 35 °C, respectively, compared with UCM treatment. AOB gene abundance and α-diversity (Chao1 and Shannon indices) were significantly increased by the application of urea and manure (P < 0.05). However, relative to UCM treatment, nitrapyrin addition treatments decreased AOB gene abundance and Chao 1 index by average 115.4 and 30.4% at 25 and 35 °C, respectively. PCA analysis showed that UCM or UCM plus nitrapyrin notably shifted AOB structure at both temperatures. However, fertilization had little effects on AOA community (P > 0.05). Potential nitrification rate (PNR) was greatly decreased by nitrapyrin addition, and PNR significantly positively correlated with AOB gene abundance (P = 0.0179 at 25 °C and P = 0.0029 at 35 °C) rather than AOA (P > 0.05). Structural equation model analysis showed that temperature directly increased AOA abundance but decrease AOB abundance, while fertilization indirectly influenced AOB community by altering soil NH4+, pH and SOC. In conclusion, the combined application of organic amendment, NBPT and nitrapyrin significantly lowered N2O emissions via reducing AOB community in calcareous soil even at high temperature. Our findings provide a solid theoretical basis in mitigating N2O emissions from calcareous soil under climate warming.

Introduction: Thrombosis is a common causal pathology for stroke, acute coronary syndrome and venous thromboembolism disorders, which are the leading cause of death worldwide. Anticoagulants have exhibited a crucial role in the prevention and treatment of thrombotic diseases. Factor Xa (FXa) is a serine protease with a central role in activating the complex blood coagulation cascade, and it is therefore regarded as an attractive target for antithrombotic agents. Areas covered: The authors review the current status of medicinal chemistry strategies for the discovery of novel FXa inhibitors and provide their expert perspectives on their future development. Expert opinion: Even if only a number of small-molecule FXa inhibitors have been reported to date, all currently available FXa inhibitors are associated with significant risk of bleeding, which may become life-threatening. There is, therefore, an urgent and unmet demand for potent novel FXa inhibitors that are potent treatments for thrombotic disorders, but which have a reduced risk of bleeding if their use is to be increasingly favored.

BACKGROUND: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases. Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases. Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.