Lutetium Lu 177 vipivotide tetraxetan for prostate cancer.

On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan), also known as 177Lu-PSMA-617, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have highly expressed prostate-specific membrane antigen (PSMA) and have at least one metastatic lesion. It is the first FDA-approved targeted radioligand therapy for eligible men with PSMA-positive mCRPC. Lutetium Lu 177 vipivotide tetraxetan is a radioligand that strongly binds to PSMA, making it ideal for treating cancers of the prostate by targeted radiation, resulting in DNA damage and cell death. PSMA is overexpressed in cancer cells while being lowly expressed in normal tissues, which makes it an ideal theranostic target. As precision medicine advances, this is a thrilling turning point for highly individualized treatments. This review aims to summarize the pharmacology and clinical studies of the novel drug lutetium Lu 177 vipivotide tetraxetan for the treatment of mCRPC, emphasizing its mechanism of action, pharmacokinetics and safety.

A Study on the Correlation Between Undergraduate Students’ Exercise Motivation, Exercise Self-Efficacy, and Exercise Behaviour Under the COVID-19 Epidemic Environment

The outbreak of COVID-19 epidemic has influenced human beings from various aspects including physical exercise behaviours. This study aims to explore the influence of the COVID-19 epidemic on exercise self-efficacy and exercise behaviour, as well as the intermediary effects of exercise motivation. A sample of 1,115 undergraduate students was investigated using the physical exercise behaviour scale, exercise self-efficacy scale, and exercise motivation scale, combined with the COVID-19 epidemic environment as an influencing factor. SPSS was used for statistical analysis and AMOS for the prediction model building. Logical analysis was undertaken to sort out and analyse the data. The structural equation model reveals that exercise self-efficacy has a positive effect on exercise motivation and exercise behaviour. Meanwhile, the COVID-19 epidemic environment negatively influences exercise behaviour through the intermediary role of exercise self-efficacy and exercise motivation. Moreover, the intermediary effect of exercise self-efficacy is greater than that of exercise self-efficacy and exercise motivation. This study provides both theoretical implications and practical guidelines for society and undergraduate students to improve their exercise behaviour during epidemic.

A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism

Animal coronaviruses (CoVs) have been identified to be the origin of Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and probably SARS-CoV-2 that cause severe to fatal diseases in humans. Variations of zoonotic coronaviruses pose potential threats to global human beings. To overcome this problem, we focused on the main protease (Mpro), which is an evolutionary conserved viral protein among different coronaviruses. The broad-spectrum anti-coronaviral drug, GC376, was repurposed to target canine coronavirus (CCoV), which causes gastrointestinal infections in dogs. We found that GC376 can efficiently block the protease activity of CCoV Mpro and can thermodynamically stabilize its folding. The structure of CCoV Mpro in complex with GC376 was subsequently determined at 2.75 Å. GC376 reacts with the catalytic residue C144 of CCoV Mpro and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV Mpro and other animal CoV Mpros with SARS-CoV-2 Mpro revealed three important structural determinants in a substrate-binding pocket that dictate entry and release of substrates. As compared with the conserved A141 of the S1 site and P188 of the S4 site in animal coronaviral Mpros, SARS-CoV-2 Mpro contains N142 and Q189 at equivalent positions which are considered to be more catalytically compatible. Furthermore, the conserved loop with residues 46–49 in animal coronaviral Mpros has been replaced by a stable α-helix in SARS-CoV-2 Mpro. In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV Mpros. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV Mpros among different species.

Effects of ACE2 and Co-factors on the Mechanism of SARS-CoV-2 Infection Among Colorectal Cancer Patients (preprint)

Background: The infection of host cells by SARS-CoV-2 is mediated by ACE2 and its co-factors, including TMPRSS2 and FURIN . Patients with cancer are highly susceptible to COVID-19 and exhibit a higher risk of severe progression. However, the mechanism of SARS-CoV-2 infection on colorectal cancer prognosis is largely unknown. Here, we investigated the role of key genes related to SARS-CoV-2 in colorectal cancer. Methods: : RNA sequencing (RNA-Seq), proteomics and single-cell RNA-Seq were used to profile the expression of ACE2 , TMPRSS2 , and FURIN in colorectal cancer. A pseudovirus was used to transfect colon cells to compare the infection rate of SARS-CoV-2 between different cell types. The TIMER database was used to analyze the association of candidate genes with immune infiltration in colorectal cancer. Cox regression model was performed to evaluate genetic effects of ACE2 on colorectal cancer prognosis. Results: : ACE2 was upregulated in colorectal cancer tissues, while TMPRSS2 and FURIN were downregulated. Increased ACE2 expression was significantly associated with a decreased tumor mutational burden. Furthermore, ACE2 promoted the SARS-CoV-2 infection in colon cancer cells than that in normal colon epithelial cells, as well as that ACE2 could affected the immune infiltration level and prognosis in colorectal cancer patients. Moreover, individuals with genetic variants in ACE2 exhibited poor overall survival of colorectal cancer. Conclusions: : These results are the first time to identify that ACE2 and its co-factors are associated with the infection and survival of colorectal cancer patients with SARS-CoV-2. Our findings would be helpful for extending the mechanisms in SARS-CoV-2 infection among colorectal cancer.

Isolating multiple formats of human monoclonal neutralizing antibodies against SARS-CoV-2 by in vitro site-directed antibody screening (preprint)

Neutralizing antibody is one of the most effective interventions for acute pathogenic infection. Currently, over three million people have been identified for SARS-CoV-2 infection but SARS-CoV-2-specific vaccines and neutralizing antibodies are still lacking. SARS-CoV-2 infects host cells by interacting with angiotensin converting enzyme-2 (ACE2) via the S1 receptor-binding domain (RBD) of its surface spike glycoprotein. Therefore, blocking the interaction of SARS-CoV-2-RBD and ACE2 by antibody would cause a directly neutralizing effect against virus. In the current study, we selected the ACE2 interface of SARS-CoV-2-RBD as the targeting epitope for neutralizing antibody screening. We performed site-directed screening by phage display and finally obtained one IgG antibody (4A3) and several domain antibodies. Among them, 4A3 and three domain antibodies (4A12, 4D5, and 4A10) were identified to act as neutralizing antibodies due to their capabilities to block the interaction between SARS-CoV-2-RBD and ACE2-positive cells. The domain antibody 4A12 was predicted to have the best accessibility to all three ACE2-interfaces on the spike homotrimer. Pseudovirus and authentic SARS-CoV-2 neutralization assays showed that all four antibodies could potently protect host cells from virus infection. Overall, we isolated multiple formats of SARS-CoV-2-neutralizing antibodies via site-directed antibody screening, which could be promising candidate drugs for the prevention and treatment of COVID-19.