ABSTRACT
The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC 50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. One-Sentence Summary A oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.
Subject(s)
COVID-19ABSTRACT
BACKGROUND: As the 2019 Coronavirus Disease (COVID-19) repeated, the prevention and treatment will be normalized in a period. "Large number of patients" and " Turnover quickly" of the day surgery ward greatly increased the difficulty of policy formulation and implementation. The normalization also had a huge negative psychological impact on patients/family members. This study aims to introduce effective epidemic prevention and control measures in day surgery wards, and to clarify the influencing factors of anxiety and subjective discomfort of patients and their families during the normalization of COVID-19. METHODS: To prepare for normalization of epidemic, research discuss improvements in the management of staff, environment, process. A total of 148 patients admitted to West China Hospital from December 2021 to March 2022 and their relatives were asked to complete a questionnaire effectively. Using the Self-rating Anxiety Scale, Social Support Rating Scale and Subjective Units of Distress scales to analyze anxiety and its risk factors. RESULTS: Under normalized control measures, no staff was infected. The subjective discomfort score was higher in people with lower body mass index (BMI). Young and high social support score were risk factors for anxiety (P < .05), and social support was positively correlated with anxiety. CONCLUSION: The normalization of epidemic is an inevitable trend in a period. A stable and safe medical environment needs to fully eliminate the policy defects, to fit the people and focus on mental health of the people. For patients/family members, who are younger,a lower BMI and higher social support should be attention more.
ABSTRACT
The global spread of SARS-CoV-2 is posing major public health challenges. One unique feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site, the function of which remains uncertain. We found that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site instead utilizes a less efficient endosomal entry pathway. This idea was supported by the identification of a suite of endosomal entry factors specific to Sdel virus by a genome-wide CRISPR-Cas9 screen. A panel of host factors regulating the surface expression of ACE2 was identified for both viruses. Using a hamster model, animal-to-animal transmission with the Sdel virus was almost completely abrogated, unlike with Sfull. These findings highlight the critical role of the S1/S2 boundary of the SARS-CoV-2 spike protein in modulating virus entry and transmission.