Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CLpro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CLpro; however, its structure lacks bonding site with active pockets of 3CLpro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CLpro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CLpro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC50) values ranging from 0.14-0.47 µM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CLpro (IC50 = 0.14 µM) and PLpro (IC50 = 0.04 µM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CLpro. The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CLpro.

Advances in the use of chlorhexidine for periodontitis treatment in diabetic patients: A review.

Periodontitis and diabetes mellitus exhibit a bidirectional relationship. This narrative review descriptively outlines the role of chlorhexidine in the periodontal treatment of diabetic patients, focusing on its antimicrobial mechanisms against microbial communities and its antiplaque effects. Although chlorhexidine is proven to be effective in combating microbial presence and improving gingivitis with substantial supporting evidence, its impact on glycemic control and insulin resistance in diabetic patients remains contentious. Additionally, the effectiveness of chlorhexidine as an adjunctive chemotherapeutic in the periodontal treatment of gestational diabetes has not yet been studied, highlighting a gap in research that necessitates further prospective studies and randomized controlled trials. Considering the interconnection between periodontal inflammation and glycemic levels, this article finally advocates for collaborative care between dental and medical professionals to manage periodontitis in diabetic patients effectively.

Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate.

SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CLpro inhibitory activity. Here, an in-depth structural optimization for JZD-07 was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CLpro inhibitory potencies with IC50 values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound 49 has the most desirable antiviral activity with EC50 of 0.272 ± 0.013 µM against the delta variant, which was more than 20 times stronger than JZD-07. Oral administration of 49 could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.

Personalized optimal nutrition lifestyle for self obesity management using metaalgorithms.

Precision medicine applies machine learning methods to estimate the personalized optimal treatment decision based on individual information, such as genetic data and medical history. The main purpose of self obesity management is to develop a personalized optimal life plan that is easy to implement and adhere to, thereby reducing the incidence of obesity and obesity-related diseases. The methodology comprises three components. First, we apply catboost, random forest and lasso covariance test to evaluate the importance of individual features in forecasting body mass index. Second, we apply metaalgorithms to estimate the personalized optimal decision on alcohol, vegetable, high caloric food and daily water intake respectively for each individual. Third, we propose new metaalgorithms named SX and SXwint learners to compute the personalized optimal decision and compare their performances with other prevailing metalearners. We find that people who receive individualized optimal treatment options not only have lower obesity levels than others, but also have lower obesity levels than those who receive 'one-for-all' treatment options. In conclusion, all metaalgorithms are effective at estimating the personalized optimal decision, where SXwint learner shows the best performance on daily water intake.

The role of transient receptor potential ankyrin 1 in age-related endothelial dysfunction.

Oxidative stress plays a key role in age-related vascular disease. The present study aimed to investigate the role of an antioxidant channel, transient receptor potential ankyrin 1 (TRPA1), in age-related endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were grown to induce replicative senescence, and 6-month-old young, 12-month-old middle-aged, and 24-month-old aged mice were used. TRPA1 was downregulated in senescent HUVECs, so were endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), and uncoupling protein 2 (UCP2). Activating TRPA1 with cinnamaldehyde prevented downregulation of eNOS, Nrf2, and UCP2, inhibited superoxide production and apoptosis, and preserved nitric oxide bioavailability in senescent HUVECs. TRPA1, phosphorylated eNOS, Nrf2 and UCP2 were significantly downregulated in aged aortas compared with young aortas after a compensatory upregulation in middle-aged aortas. Dietary administration of cinnamaldehyde for 12 months prevented mitochondrial dysfunction, improved endothelium-dependent relaxation, and increased expression of eNOS, Nrf2, and UCP2 in aged aortas. Importantly, the effects of cinnamaldehyde can be blocked by a TRPA1 antagonist HC-030031. These findings suggest that TRPA1 may play a critical role in age-related endothelial dysfunction and may become a therapeutic target for the treatment and prevention of age-related vascular disease.