Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2.

The 3C-like protease (3CLpro) is essential for the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it a promising target for the treatment of corona virus disease 2019 (COVID-19). In this study, a series of 2,3,5-substituted [1,2,4]-thiadiazole analogs were discovered to be able to inhibit 3CLpro as non-peptidomimetic covalent binders at submicromolar levels, with IC50 values ranging from 0.118 to 0.582 µM. Interestingly, these compounds were also shown to inhibit PLpro with the same level of IC50 values, but had negligible effect on proteases such as chymotrypsin, cathepsin B, and cathepsin L. Subsequently, the antiviral abilities of these compounds were evaluated in cell-based assays, and compound 6g showed potent antiviral activity with an EC50 value of 7.249 µM. It was proposed that these compounds covalently bind to the catalytic cysteine 145 via a ring-opening metathesis reaction mechanism. To understand this covalent-binding reaction, we chose compound 6a, one of the identified hit compounds, as a representative to investigate the reaction mechanism in detail by combing several computational predictions and experimental validation. The process of ring-opening metathesis was theoretically studied using quantum chemistry calculations according to the transition state theory. Our study revealed that the 2,3,5-substituted [1,2,4]-thiadiazole group could covalently modify the catalytic cysteine in the binding pocket of 3CLpro as a potential warhead. Moreover, 6a was a known GPCR modulator, and our study is also a successful computational method-based drug-repurposing study.

Effects of Emotional Expressiveness of a Female Digital Human on Loneliness, Stress, Perceived Support, and Closeness Across Genders: Randomized Controlled Trial.

BACKGROUND: Loneliness is a growing public health problem that has been exacerbated in vulnerable groups during the COVID-19 pandemic. Social support interventions have been shown to reduce loneliness, including when delivered through technology. Digital humans are a new type of computer agent that show promise as supportive peers in health care. For digital humans to be effective and engaging support persons, it is important that they develop closeness with people. Closeness can be increased by emotional expressiveness, particularly in female relationships. However, it is unknown whether emotional expressiveness improves relationships with digital humans and affects physiological responses. OBJECTIVE: The aim of this study is to investigate whether emotional expression by a digital human can affect psychological and physiological outcomes and whether the effects are moderated by the user's gender. METHODS: A community sample of 198 adults (101 women, 95 men, and 2 gender-diverse individuals) was block-randomized by gender to complete a 15-minute self-disclosure conversation with a female digital human in 1 of 6 conditions. In these conditions, the digital human varied in modality richness and emotional expression on the face and in the voice (emotional, neutral, or no face; emotional or neutral voice). Perceived loneliness, closeness, social support, caring perceptions, and stress were measured after each interaction. Heart rate, skin temperature, and electrodermal activity were assessed during each interaction. 3-way factorial analyses of variance with post hoc tests were conducted. RESULTS: Emotional expression in the voice was associated with greater perceptions of caring and physiological arousal during the interaction, and unexpectedly, with lower feelings of support. User gender moderated the effect of emotional expressiveness on several outcomes. For women, an emotional voice was associated with increased closeness, social support, and caring perceptions, whereas for men, a neutral voice increased these outcomes. For women, interacting with a neutral face was associated with lower loneliness and subjective stress compared with no face. Interacting with no face (ie, a voice-only black screen) resulted in lower loneliness and subjective stress for men, compared with a neutral or emotional face. No significant results were found for heart rate or skin temperature. However, average electrodermal activity was significantly higher for men while interacting with an emotional voice. CONCLUSIONS: Emotional expressiveness in a female digital human has different effects on loneliness, social, and physiological outcomes for men and women. The results inform the design of digital human support persons and have theoretical implications. Further research is needed to evaluate how more pronounced emotional facial expressions in a digital human might affect the results. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000865819; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381816&isReview.

Efficacy and Safety of Washed Microbiota Transplantation to Treat Patients with Mild-to-Severe COVID-19 and Suspected of Having Gut Microbiota Dysbiosis: Study Protocol for a Randomized Controlled Trial.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is often accompanied by gastrointestinal symptoms, which are related to gut microbiota dysbiosis (GMD). Whether washed microbiota transplantation (WMT) is an effective treatment for COVID-19 patients suspected of having GMD by restoring the gut microbiota is unknown. This study is designed to explore the efficacy and safety of WMT in COVID-19 patients suspected of having GMD. METHODS: This is a randomized, multicenter, single-blind prospective study. COVID-19 patients suspected of having GMD will be randomly divided to receive routine treatment only or to receive routine treatment and WMT. The frequency of WMT will be once a day for three consecutive days. Laboratory and imaging examinations will be performed at admission, 1 and 2 weeks after treatment, and on the day of discharge. Then a telephone follow-up will be conducted at 1st week, 2nd week, and 6th month after discharge. The clinical efficacy and safety of WMT in COVD-19 patients suspected of having GMD and the effects of WMT on the organ function, homeostasis, inflammatory response, intestinal mucosal barrier function, and immunity of the patients will be evaluated. RESULTS: By following the proposed protocol, WMT is expected to be efficacious and safe for the treatment of COVID-19 patients suspected of having GMD, and the therapeutic effect is expected to be associated with improvement of the intestinal mucosal barrier function, inflammatory response, and immunity. CONCLUSION: The findings from this study may offer a new approach for the prevention and treatment of COVID-19 patients suspected of having GMD.