The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.

Abstract: Chronic infection of hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC) in China. The occurrence of HCC through chronic inflammation follows the Darwinian evolutionary law, known as "mutation-selection-adaptation". Inflammatory mutagenic molecules promote the generation of somatic mutations, and the most mutant cells are eliminated by inflammatory microenvironment. However, a minority of mutant cells survive the selective pressure and develop to tumor initial cells by activating oncogenic signaling pathway and acquiring "stemness" characteristics. Alongside this process, HBV also evolves under the pressure of inflammatory microenvironment, which is characterized by the accumulation of cancer-promoting viral mutations, reducing the ability to infect new individuals. The high-risk mutant strains are eliminated with the death of hosts, leading to a phenomenon termed as "dead-end evolution". HBV evolution contributes to cancer evolution by maintaining the inflammatory microenvironment, activating oncogenic pathways, inducing somatic cell mutations, and altering metabolic patterns. The combo mutations of HBV and HBV integrations can be applied to predict the occurrence and prognosis of HCC. Anti-viral treatment reduces the risk of HCC by relieving inflammation. This article reviews the molecular epidemiological evidence and mechanistic advances related to the co-evolution of HBV and HCC. Clarifying the co-evolutionary pattern of virus and cancer and the key molecular events involved, is beneficial for identifying new biomarkers and therapeutic targets, thus improving the prevention and treatment strategies for HCC.

Objective To investigate the renoprotective effects of a Sichuan dark tea-based medicated dietary formula(alternatively referred to as Qing,or clarity in Chinese)on mice with diet-induced obesity(DIO)and to explore the specific mechanisms involved.Methods Male C57BL/6 mice were randomly assigned to three groups,a control group,a DIO group,and a Qing treatment group,or the Qing group,with 8 mice in each group.The mice in the control group were given normal maintenance feed and purified water,and the other two groups were fed a high-fat diet for 12 weeks to establish the DIO model.After that,high-fat diet continued in the DIO group,while the Qing group was given Qing at the same time for 12 weeks,during which period the weight of the mice was monitored and recorded every week.The mice were sacrificed after 12 weeks.Serum samples were collected and the levels of triglyceride(TG),total cholesterol(TC),alanine aminotransferase(ALT),aspartate aminotransferase(AST),and albumin were measured to evaluate liver function.In addition,renal lipids were extracted to determine the levels of TG and TC in the kidney and periodic acid-Schiff(PAS)and oil red O stainings were performed to evaluate kidney pathological injury.Western blot was performed to determine the phosphorylated AMPK(pAMPK)/AMPK ratio in the kidney tissue.RT-qPCR and Western blot were used to determine the expression of proteins related to fatty acid oxidation,including acetyl-CoA carboxylase 1(ACC1),carnitine acyltransferase 1(CTP1),peroxisome proliferators-activated receptor γ(PPARγ),peroxisome proliferators-activated receptor-1 α(PPAR1α),sterol-regulatory element binding proteins(SREBP-1),and key proteins related to lipid synthesis,including fatty acid synthase(FASN)and stearoyl-coenzyme A desaturase 1(stearoyl-CoA desaturase)in the kidney tissue.16SrRNA and metabolomics were applied to analyze the gut microbiota in the intestinal contents and its metabolites.Results Compared with those of the control group,the levels of liver mass(P=0.000 3),serum ALT(P＜0.000 1)and AST(P=0.0001),and kidney TC(P=0.0191)and TG(P=0.0101)of the DIO group were significantly increased and there was lipid deposition in the kidney.Compared with those of the DIO group,mice in the Qing group showed effective reduction in liver mass(P=0.0316)and improvements in the abnormal serum levels of AST(P=0.0012)and ALT(P=0.002 7)and kidney TC(P=0.0200)and TG(P=0.0499).In addition,mice in the Qing group showed significant improvement in lipid deposition in the kidney.Qing group showed increased pAMPK/AMPK ratio in comparison with that of the DIO group.In comparison with those of the control group,mice in the DIO group had upregulated expression of lipid synthesis-related genes and proteins(SREBP-1,FASN,and SCD1).As for the fatty acid oxidation-related genes and proteins,DIO mice showed upregulated expression of ACC1 and downregulated expression of CPT1A,PPARy,and PGC1α in comparison with those of the control group.In the Qing goup,improvements in regard to all these changes were observed.The Qing group demonstrated improvement in the disrupted homeostasis of the gut microbiota.Short-chain fatty acids in the cecal contents,especially isovaleric acid and propionic acid,were also restored.Conclusion Sichuan dark tea-based medicated dietary formula may improve renal lipid metabolism by regulating gut microbiota and the levels of intestinal short-chain fatty acids,thereby protecting obesity-related kidney injury.Isovaleric acid and propionic acid may be the metabolites key to its regulation of gut microbiota.

A novel coronavirus pneumonia (NCP) epidemic has occurred in Wuhan, Hubei Province since December 2019, caused by a novel coronavirus (2019-nCoV) never been seen previously in human. China has imposed the strictest quarantine and closed management measures in history to control the spreading of the disease. However, severe trauma can still occur in the NCP patients. In order to standardize the emergency treatment and the infection prevention and control of severe trauma patients with hidden infection, suspected or confirmed infection of 2019-nCoV, Trauma Surgery Branch of Chinese Medical Doctors' Association organized this expert consensus. The consensus illustrated the classification of the NCP patients, severe trauma patients in need of emergency surgery, emergency surgery type, hierarchical protection for medical personnel and treatment places. Meanwhile, the consensus standardized the screening, injury severity evaluation, emergency surgical treatment strategy and postoperative management strategy of severe trauma patients during the epidemic period of NCP, providing a basis for the clinical treatment of such kind of patients.