Human embryonic stem cell-derived cardiomyocytes express SARS-CoV-2 host entry proteins: screen to identify inhibitors of infection (preprint)

Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection.

Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease (preprint)

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19). We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 convalescent donors, C121 and C135. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins (preprint)

Motivation: Recent efforts to computationally identify inhibitors for SARS-CoV-2 proteins have largely ignored the issue of receptor flexibility. We have implemented a computational tool for ensemble docking with the SARS-CoV-2 proteins, including the main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp). Results: Ensembles of other SARS-CoV-2 proteins are being prepared and made available through a user-friendly docking interface. Plausible binding modes between conformations of a selected ensemble and an uploaded ligand are generated by DINC, our parallelized meta-docking tool. Binding modes are scored with three scoring functions, and account for the flexibility of both the ligand and receptor. Additional details on our methods are provided in the supplementary material. Availability: dinc-covid.kavrakilab.org . Supplementary information: Details on methods for ensemble generation and docking are provided as supplementary data online.

The psychosocial impact of the COVID-19 pandemic on 4,378 UK healthcare workers and ancillary staff: initial baseline data from a cohort study collected during the first wave of the pandemic. (preprint)

Objectives This study reports preliminary findings on the prevalence of, and factors associated with, mental health and wellbeing outcomes of healthcare workers during the early months (April-June) of the COVID-19 pandemic in the UK. Methods Preliminary cross-sectional data were analysed from a cohort study (n=4,378). Clinical and non-clinical staff of three London-based NHS Trusts (UK), including acute and mental health Trusts, took part in an online baseline survey. The primary outcome measure used is the presence of probable common mental disorders (CMDs), measured by the General Health Questionnaire (GHQ-12). Secondary outcomes are probable anxiety (GAD-7), depression (PHQ-9), Post-Traumatic Stress Disorder (PTSD) (PCL-6), suicidal ideation (CIS-R), and alcohol use (AUDIT). Moral injury is measured using the Moray Injury Event Scale (MIES). Results Analyses showed substantial levels of CMDs (58.9%, 95%CI 58.1 to 60.8), and of PTSD (30.2%, 95%CI 28.1 to 32.5) with lower levels of depression (27.3%, 95%CI 25.3 to 29.4), anxiety (23.2%, 95%CI 21.3 to 25.3), and alcohol misuse (10.5%, 95%CI, 9.2 to 11.9). Women, younger staff, and nurses tended to have poorer outcomes than other staff, except for alcohol misuse. Higher reported exposure to moral injury (distress resulting from violation of one's moral code) was strongly associated with increased levels of CMDs, anxiety, depression, PTSD symptoms, and alcohol misuse. Conclusions Our findings suggest that mental health support for healthcare workers should consider those demographics and occupations at highest risk. Rigorous longitudinal data are needed in order to respond to the potential long-term mental health impacts of the pandemic.

Insights from Genomes and Genetic Epidemiology of SARS-CoV-2 isolates from the state of Andhra Pradesh (preprint)

Coronavirus disease (COVID-19) emerged from a city in China and has now spread as a global pandemic affecting millions of individuals. The causative agent, SARS-CoV-2 is being extensively studied in terms of its genetic epidemiology using genomic approaches. Andhra Pradesh is one of the major states of India with the third-largest number of COVID-19 cases with limited understanding of its genetic epidemiology. In this study, we have sequenced 293 SARS-CoV-2 genome isolates from Andhra Pradesh with a mean coverage of 13,324X. We identified 564 high-quality SARS-CoV-2 variants, out of which 15 are novel. A total of 18 variants mapped to RT-PCR primer/probe sites, and 4 variants are known to be associated with an increase in infectivity. Phylogenetic analysis of the genomes revealed the circulating SARS-CoV-2 in Andhra Pradesh majorly clustered under the clade A2a (94%), while 6% fall under the I/A3i clade, a clade previously defined to be present in large numbers in India. To the best of our knowledge, this is the most comprehensive genetic epidemiological analysis performed for the state of Andhra Pradesh.