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.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

Objective:To virtual screen the active ingredient of Shenmai injection in treatment of Novel Coronavirus Pneumonia and discuss the potential mechanism based on network pharmacology and high throughput molecular docking. Methods:Based on network pharmacology and high-throughput molecular docking technology, the compounds and predicted targets of Shenmai injection were retrieved from TCMSP, BATMAN-TCM and Targetnet databases, and the composition target map was constructed. The genes related to coronavirus pneumonia were retrieved from OMIM and GeneCards databases, and the PPI network between target genes was constructed by searching the common parts of target genes; David 6.8 was used to analyze gene function and pathway enrichment, and PDB database was used to obtain protein crystal structure, and Autodock Vina and python scripts were used for high-throughput molecular docking. Results:A total of 27 compounds and 224 target genes were obtained. 15 core components and 15 core targets for the treatment of coronavirus pneumonia were identified: CASP3, NOS2, PARP1, CASP8, NOS3, BCL2, ADA, OPRM1, TGFB1, TLR9, ACHE, SLC29A1, BAX, ADK, and PNP. The enrichment analysis showed that the core targets acted on the signaling pathways such as Tuberculosis, Pathways in cancer, Hepatitis B and Apoptosis. The better components of Novel Coronavirus Pneumonia related targets were diosgenin, stigmasterol, beta-sitosterol and ginsenoside Rh1_qt obtained by virtual screening.Conclusion:This study screened out the active ingredient and tarket of Shenmai Injection in treatment of Novel Coronavirus Pneumonia. It laid a foundation for the further clinical application of Shenmai injection and development of novel coronavirus pneumonia drugs.

Objective:With network pharmacology, this paper aims to explore the potential active constituents, related targets and signal pathways to elucidate the mechanism of Calyx seu Fructus Physalis in the treatment of lung cancer. Methods:By searching for Pharmacology Database of Traditional Chinese Medicine Systems and Analysis Platform (TCMSP) to obtain the active constituents of Calyx seu Fructus Physalis, and predict the target genes of active constituents by using SWISS and SEA. By collecting the corresponding targets approved by FDA and search for different database, including Therapeutic Target Database (TTD), Database of Gene-disease Associations (DisGeNET) and Online Mendelian Inheritance in OMIM to build a database of lung cancer related target genes; To get the target genes of herb-disease proteins by the intersection of the two databases and display the results through the network software of Cytoscape 3.7.2. Then to use the Database of Annotation, Visualization and Integrated Discovery (DAVID) to conduct key enrichment analysis of Kyoto Gene and Genome Encyclopedia (KEGG) pathway enrichment analysis. Combining related literature to analize the active ingredients and mechanism of Calyx seu Fructus Physalis in the prevention and treatment of lung cancer. Results:It was found that 11 active constituents of Calyx seu Fructus Physalis could play the role of anti-lung cancer by regulating 19 lung cancer related targets such as EGFR, ESR1, MDM2, MMP2 and MET. There were 15 signal pathways involved Proteoglycans in cancer, MicroRNAs in cancer, Pathways in cancer, Transcriptional misregulation in cancer, PI3K-Akt signaling pathway and other key signal pathways. Conclusion:The results show that the active constituents of anti-lung cancer effect of Calyx seu Fructus Physalis may be Oleic acid, Cycloartenol, Obturator, Graminesterol, β-sitosterol, etc. The mechanism of action may be related to multiple cancer-related signaling pathways such as Proteoglycans pathway, Transcriptional misregulation pathway, and PI3K-Akt signaling pathway.

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

In this report, a series of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

Objective:To analyze the influencing factors of prognosis of patients with diabetic kidney disease (DKD) in intensive care unit (ICU), and analyze their predictive value.Methods:Based on the inpatient information of more than 50 000 patients from June 2001 to October 2012 in the latest version of American Intensive Care Medical Information Database (MIMIC-Ⅲ v1.4), the data of DKD patients were screened out, including gender, age, body weight, comorbidities [hypertension, coronary heart disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD)], sequential organ failure assessment (SOFA) score, the length of ICU stay, the incidence of mechanical ventilation, vasoactive drugs and renal replacement therapy during the ICU hospitalization, complications of other diseases [ventilator-associated pneumonia (VAP), urinary tract infection (UTI), diabetic ketoacidosis (DKA), acute myocardial infarction (AKI)] and prognosis of ICU. At the same time, the blood routine and biochemical data of the first 24 hours in ICU and the extremum values during the ICU hospitalization were collected. Multivariate Logistic regression analysis was used to screen the prognostic factors of DKD patients in ICU, and receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of death risk factors.Results:416 DKD patients were screened out, 20 patients were excluded due to data missing, and finally 396 patients were enrolled, including 220 survival patients and 176 dead patients. Compared with the survival group, the patients in the death group were older (years old: 57.13±13.04 vs. 52.61±14.15), with lower rates of hypertension and CKD (11.4% vs. 23.6%, 26.7% vs. 41.4%), higher SOFA scores and baseline values of blood urea nitrogen (BUN), serum creatinine (SCr) and blood K + [SOFA score: 5.86±2.79 vs. 4.49±2.56, BUN (mmol/L): 18.4±10.0 vs. 14.8±9.0, SCr (μmol/L): 387.2±382.8 vs. 284.6±244.9, K + (mmol/L): 4.64±0.99 vs. 4.33±0.86], and longer ICU stay [days: 2.65 (1.48, 5.21) vs. 2.00 (1.00, 4.00)], and the differences were statistically significant (all P < 0.01). Further analysis of laboratory tests extremum values during ICU hospitalization showed that the maximum (max) and minimum (min) values of white blood cell (WBC), BUN and SCr, and K +max in the death group were significantly higher than those in the survival group [WBC max (×10 9/L): 17.3±10.3 vs. 14.5±7.3, WBC min (×10 9/L): 7.9±4.1 vs. 6.7±2.7, BUN max (mmol/L): 23.8±10.4 vs. 18.8±10.2, BUN min (mmol/L): 11.0±6.6 vs. 9.3±6.6, SCr max (μmol/L): 459.7±392.5 vs. 350.1±294.4, SCr min (μmol/L): 246.6±180.3 vs. 206.9±195.4, K +max (mmol/L): 5.35±0.93 vs. 5.09±0.99], and the minimum values of hemoglobin (Hb min) and glucose (Glu min) were significantly lower than those in the survival group [Hb min (g/L): 87.4±14.5 vs. 90.6±16.5, Glu min (mmol/L): 4.0±1.7 vs. 4.6±2.0], and the differences were statistically significant (all P < 0.05). The incidences of mechanical ventilation and vasoactive drugs during ICU hospitalization in the death group were significantly higher than those in the survival group (37.5% vs. 24.1%, 32.4% vs. 20.0%, both P < 0.01), and the incidences of UTI and AMI in the death group were significantly higher than those in the survival group (29.5% vs. 19.1%, 8.5% vs. 3.6%, both P < 0.05). Multivariate Logistic regression analysis showed that age [odds ratio ( OR) = 1.019, 95% confidence interval (95% CI) was 1.003-1.036, P = 0.023], SOFA score ( OR = 1.142, 95% CI was 1.105-1.246, P = 0.003), WBC min ( OR = 1.134, 95% CI was 1.054-1.221, P = 0.001) and BUN max ( OR = 1.010, 95% CI was 1.002-1.018, P = 0.018) were risk factors of death of DKD patients in ICU. ROC curve analysis showed that the area under ROC curve (AUC) of combination of risks factors of death was 0.706, the sensitivity was 61.6%, and the specificity was 73.2%. Conclusions:In order to prevent DKD patients from getting worse in ICU, we should pay close attention to the blood biochemical indexes, especially the renal function indexes, and give timely treatment. At the same time, we should actively prevent the occurrence of complications such as infection and cardiovascular disease.

Objective:To observe preventive effect of intestinal stent against anastomotic leakage after rectal cancer operation.Methods:A retrospective cohort study was carried out. Clinical data of 107 patients with low rectal cancer undergoing laparoscopic radical resection from January 2015 to August 2019 were retrospectively analyzed. Intestinal stent was placed intraoperatively in 48 cases and was not placed in 59 cases. Postoperative Wexner score for anal function and incidence of anastomotic leakage were compared between patients with and without intstinal stent.Results:There was no significant differences in age, distance between tumor and the anal verge, operative time and postoperative Wexner score for anal function between the two groups (all P>0.05). After a month of follow-up, the incidence of anastomotic leakage was 16.9% (10/59) in the non-stent group, while no anastomotic leakage was found in the stent group ( P=0.002). Conclusion:Placement of intestinal stent can effectively prevent anastomotic leakage after low rectal cancer surgery.

Objective:To observe preventive effect of intestinal stent against anastomotic leakage after rectal cancer operation.Methods:A retrospective cohort study was carried out. Clinical data of 107 patients with low rectal cancer undergoing laparoscopic radical resection from January 2015 to August 2019 were retrospectively analyzed. Intestinal stent was placed intraoperatively in 48 cases and was not placed in 59 cases. Postoperative Wexner score for anal function and incidence of anastomotic leakage were compared between patients with and without intstinal stent.Results:There was no significant differences in age, distance between tumor and the anal verge, operative time and postoperative Wexner score for anal function between the two groups (all P>0.05). After a month of follow-up, the incidence of anastomotic leakage was 16.9% (10/59) in the non-stent group, while no anastomotic leakage was found in the stent group ( P=0.002). Conclusion:Placement of intestinal stent can effectively prevent anastomotic leakage after low rectal cancer surgery.

Objective: To elucidate the expression levels of key immune biomarkers, phosphate and tension homology deleted on chromosome ten (PTEN) and programmed cell death protein1(PD-1),of different immune tolerance pathway in classic Hodgkin’s lymphoma (CHL) to further determine their clinical role and prognostic significance. Methods: The clinical features and prognostic factors of 56 CHL patients, who were admitted to the TianJin Medical University Cancer Institute from February 2003 to August 2013, were retrospectively analyzed. PTEN and PD-1 protein expression levels were analyzed by immunohistochemistry, Epstein-Barr virus encoded RNA (EBER) was performed by in situ hybridization assay. Correlations between the expression of biomarkers and clinicopathologic parameters were examined and survival analyses were performed. Results: This cohort of 56 CHL patients included 34 males and 22 females with a median age of 25 years (ranged from 7 to 71 years). In a univariate analysis, age≥45, IPS score >2, EBER positive, high expression of PTEN protein conferred inferior 5-year OS and 5-year PFS; In a multivariate model, age≥45, IPS score >2, EBER positive, high expression of PTEN protein were identified as the independent adverse prognostic factors for CHL. Conclusions This study suggested for the first time that PTEN was independent prognostic immune biomarkers in CHL, which provided the novel therapeutic strategy of immune therapy for CHL.