Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation.

Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19. Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking. Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC50 values ranging from 0.6 to 2.4 µM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site. Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.

Model Evaluation of Secondary Chemistry due to Disinfection of Indoor Air with Germicidal Ultraviolet Lamps

Air disinfection using germicidal ultraviolet light (GUV) has received increasing attention during the COVID-19 pandemic. GUV uses UVC lamps to inactivate microorganisms, but it also initiates photochemistry in air. However, GUV's indoor-air-quality impact has not been investigated in detail. Here, we model the chemistry initiated by GUV at 254 ("GUV254") or 222 nm ("GUV222") in a typical indoor setting for different ventilation levels. Our analysis shows that GUV254, usually installed in the upper room, can significantly photolyze O3, generating OH radicals that oxidize indoor volatile organic compounds (VOCs) into more oxidized VOCs. Secondary organic aerosol (SOA) is also formed as a VOC-oxidation product. GUV254-induced SOA formation is of the order of 0.1-1 mu g/m3 for the cases studied here. GUV222 (described by some as harmless to humans and thus applicable for the whole room) with the same effective virus-removal rate makes a smaller indoor-air-quality impact at mid-to-high ventilation rates. This is mainly because of the lower UV irradiance needed and also less efficient OH-generating O3 photolysis than GUV254. GUV222 has a higher impact than GUV254 under poor ventilation due to a small but significant photochemical production of O3 at 222 nm, which does not occur with GUV254.

Examining the asymmetries between equity and commodity ETFs during COVID-19

Previous studies have neither examined the volatility co-movements across stock and commodity markets in terms of both time and frequency nor differentiated between bad and good volatility and the potential asymmetric effect. To address this gap, we computed 5-min price data, the positive and negative semivariances on five leading Exchange Traded Funds (ETFs) covering the US equity market, crude oil, natural gas, gold, and silver markets from January 2, 2019 to May 29, 2020, and then draw on the wavelet coherency methodology and the time-varying wavelet coherence measure. The results showed that the negative realized volatility co-movements are stronger during the COVID-19 outbreak, especially at short and medium frequencies. The US stock market leads energy and precious metals in the short-run frequency. However, over the long-run, the lead-lag pattern mostly alternates over time for all cases. Notably, the realized volatilities of US equities and precious metals are shaped by the COVID-19 outbreak, reflecting the quest of investors for protection from the market volatilities by investing in gold and silver. This latest finding is confirmed by the wavelet coherence measure. Further results showed asymmetric co-movements emanating especially from realized negative semivariance of equities and energy markets around the pandemic outbreak across short time horizons. We also noticed that the COVID-19 outbreak increased the procyclical movement of all ETFs in the short term. The effect is more pronounced among the US equity and precious metals markets, whereas no significant countercyclical connectedness is observed among these markets. Our findings supported previous evidence that gold and silver can serve as safe-haven assets due to their low coherence with other assets.

Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation

Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19. Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking. Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC50 values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site. Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.

Transmission and containment of the SARS-CoV-2 Delta variant of concern in Guangzhou, China: A population-based study.

BACKGROUND: The first community transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant of concern (VOC) in Guangzhou, China occurred between May and June 2021. Herein, we describe the epidemiological characteristics of this outbreak and evaluate the implemented containment measures against this outbreak. METHODOLOGY/PRINCIPAL FINDINGS: Guangzhou Center for Disease Control and Prevention provided the data on SARS-CoV-2 infections reported between 21 May and 24 June 2021. We estimated the incubation period distribution by fitting a gamma distribution to the data, while the serial interval distribution was estimated by fitting a normal distribution. The instantaneous effective reproductive number (Rt) was estimated to reflect the transmissibility of SARS-CoV-2. Clinical severity was compared for cases with different vaccination statuses using an ordinal regression model after controlling for age. Of the reported local cases, 7/153 (4.6%) were asymptomatic. The median incubation period was 6.02 (95% confidence interval [CI]: 5.42-6.71) days and the means of serial intervals decreased from 5.19 (95% CI: 4.29-6.11) to 3.78 (95% CI: 2.74-4.81) days. The incubation period increased with age (P<0.001). A hierarchical prevention and control strategy against COVID-19 was implemented in Guangzhou, with Rt decreasing from 6.83 (95% credible interval [CrI]: 3.98-10.44) for the 7-day time window ending on 27 May 2021 to below 1 for the time window ending on 8 June and thereafter. Individuals with partial or full vaccination schedules with BBIBP-CorV or CoronaVac accounted for 15.3% of the COVID-19 cases. Clinical symptoms were milder in partially or fully vaccinated cases than in unvaccinated cases (odds ratio [OR] = 0.26 [95% CI: 0.07-0.94]). CONCLUSIONS/SIGNIFICANCE: The hierarchical prevention and control strategy against COVID-19 in Guangzhou was timely and effective. Authorised inactivated vaccines are likely to contribute to reducing the probability of developing severe disease. Our findings have important implications for the containment of COVID-19.

Effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a test-negative case-control real-world study.

The effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant, which has been associated with greater transmissibility and virulence, remains unclear. We conducted a test-negative case-control study to explore the vaccine effectiveness (VE) in real-world settings. We recruited participants aged 18-59 years who consisted of SARS-CoV-2 test-positive cases (n = 74) and test-negative controls (n = 292) during the outbreak of the Delta variant in May 2021 in Guangzhou city, China. Vaccination status was compared to estimate The VE of SARS-CoV-2 inactivated vaccines. A single dose of inactivated SARS-CoV-2 vaccine yielded the VE of only 13.8%. After adjusting for age and sex, the overall VE for two-dose vaccination was 59.0% (95% confidence interval: 16.0% to 81.6%) against coronavirus disease 2019 (COVID-19) and 70.2% (95% confidence interval: 29.6-89.3%) against moderate COVID-19 and 100% against severe COVID-19 which might be overestimated due to the small sample size. The VE of two-dose vaccination against COVID-19 reached 72.5% among participants aged 40-59 years, and was higher in females than in males against COVID-19 and moderate diseases. While single dose vaccination was not sufficiently protective, the two-dose dosing scheme of the inactivated vaccines was effective against the Delta variant infection in real-world settings, with the estimated efficacy exceeding the World Health Organization minimal threshold of 50%.

Immunothrombosis in Acute Respiratory Dysfunction of COVID-19.

COVID-19 is an acute, complex disorder that was caused by a new ß-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on current reports, it was surprising that the characteristics of many patients with COVID-19, who fulfil the Berlin criteria for acute respiratory distress syndrome (ARDS), are not always like those of patients with typical ARDS and can change over time. While the mechanisms of COVID-19-related respiratory dysfunction in COVID-19 have not yet been fully elucidated, pulmonary microvascular thrombosis is speculated to be involved. Considering that thrombosis is highly related to other inflammatory lung diseases, immunothrombosis, a two-way process that links coagulation and inflammation, seems to be involved in the pathophysiology of COVID-19, including respiratory dysfunction. Thus, the current manuscript will describe the proinflammatory milieu in COVID-19, summarize current evidence of thrombosis in COVID-19, and discuss possible interactions between these two.

Temporal dynamic in the impact of COVID- 19 outbreak on cause-specific mortality in Guangzhou, China.

BACKGROUND: Studies related to the SARS-CoV-2 spikes in the past few months, while there are limited studies on the entire outbreak-suppressed cycle of COVID-19. We estimate the cause-specific excess mortality during the complete circle of COVID-19 outbreak in Guangzhou, China, stratified by sociodemographic status. METHODS: Guangzhou Center for Disease Control Prevention provided the individual data of deaths in Guangzhou from 1 January 2018 through 30 June 2020. We applied Poisson regression models to daily cause-specific mortality between 1 January 2018 and 20 January 2020, accounting for effects of population size, calendar time, holiday, ambient temperature and PM2.5. Expected mortality was estimated for the period from 21 January through 30 June 2020 assuming that the effects of factors aforementioned remained the same as described in the models. Excess mortality was defined as the difference between the observed mortality and the expected mortality. Subgroup analyses were performed by place of death, age group, sex, marital status and occupation class. RESULTS: From 21 January (the date on which the first COVID-19 case occurred in Guangzhou) through 30 June 2020, there were three stages of COVID-19: first wave, second wave, and recovery stage, starting on 21 January, 11 March, and 17 May 2020, respectively. Mortality deficits were seen from late February through early April and in most of the time in the recovery stage. Excesses in hypertension deaths occurred immediately after the starting weeks of the two waves. Overall, we estimated a deficit of 1051 (95% eCI: 580, 1558) in all-cause deaths. Particularly, comparing with the expected mortality in the absence of COVID-19 outbreak, the observed deaths from pneumonia and influenza substantially decreased by 49.2%, while deaths due to hypertension and myocardial infarction increased by 14.5 and 8.6%, respectively. In-hospital all-cause deaths dropped by 10.2%. There were discrepancies by age, marital status and occupation class in the excess mortality during the COVID-19 outbreak. CONCLUSIONS: The excess deaths during the COVID-19 outbreak varied by cause of death and changed temporally. Overall, there was a deficit in deaths during the study period. Our findings can inform preparedness measures in different stages of the outbreak.

Genomic Elucidation of a COVID-19 Resurgence and Local Transmission of SARS-CoV-2 in Guangzhou, China.

While China experienced a peak and decline in coronavirus disease 2019 (COVID-19) cases at the start of 2020, regional outbreaks continuously emerged in subsequent months. Resurgences of COVID-19 have also been observed in many other countries. In Guangzhou, China, a small outbreak, involving less than 100 residents, emerged in March and April 2020, and comprehensive and near-real-time genomic surveillance of SARS-CoV-2 was conducted. When the numbers of confirmed cases among overseas travelers increased, public health measures were enhanced by shifting from self-quarantine to central quarantine and SARS-CoV-2 testing for all overseas travelers. In an analysis of 109 imported cases, we found diverse viral variants distributed in the global viral phylogeny, which were frequently shared within households but not among passengers on the same flight. In contrast to the viral diversity of imported cases, local transmission was predominately attributed to two specific variants imported from Africa, including local cases that reported no direct or indirect contact with imported cases. The introduction events of the virus were identified or deduced before the enhanced measures were taken. These results show the interventions were effective in containing the spread of SARS-CoV-2, and they rule out the possibility of cryptic transmission of viral variants from the first wave in January and February 2020. Our study provides evidence and emphasizes the importance of controls for overseas travelers in the context of the pandemic and exemplifies how viral genomic data can facilitate COVID-19 surveillance and inform public health mitigation strategies.

Asymmetric volatility spillover among Chinese sectors during COVID-19.

Inter-sectoral volatility linkages in the Chinese stock market are understudied, especially asymmetries in realized volatility connectedness, accounting for the catastrophic event associated with the COVID-19 outbreak. In this paper, we examine the asymmetric volatility spillover among Chinese stock market sectors during the COVID-19 pandemic using 1-min data from January 2, 2019 to September 30, 2020. In doing so, we build networks of generalized forecast error variances by decomposition of a vector autoregressive model, controlling for overall market movements. Our results show evidence of the asymmetric impact of good and bad volatilities, which are found to be time-varying and substantially intense during the COVID-19 period. Notably, bad volatility spillover shocks dominate good volatility spillover shocks. The findings are useful for Chinese investors and portfolio managers constructing risk hedging portfolios across sectors and for Chinese policymakers monitoring and crafting stimulating policies for the stock market at the sectoral level.

Asymmetric efficiency of cryptocurrencies during COVID19.

In this study, we examine the asymmetric efficiency of cryptocurrencies using 1-hour data of Bitcoin, Ethereum, Litecoin, and Ripple. In doing so, we utilize the asymmetric multifractal detrended fluctuation analysis (MF-DFA). We find significant asymmetric multifractality in the price of cryptocurrencies and that upward trends exhibit stronger multifractality than downward trends. Using the time-varying deficiency measure, we show that the COVID-19 outbreak adversely affected the efficiency of the four cryptocurrencies, given a substantial increase in the levels of inefficiency during the COVID-19 period. Bitcoin and Ethereum are the hardest hit, and at the same time, these two largest cryptocurrencies recovered faster at the end of March 2020 from their sharp dip towards inefficiency. The findings confirm previous evidence that market efficiency is time varying; also, unprecedented catastrophic events, such as the COVID-19 outbreak, have adverse effects of on the efficiency of leading cryptocurrencies.

Genomic surveillance of a resurgence of COVID-19 in Guangzhou, China (preprint)

In the middle of March, the World Health Organization declared the outbreak of COVID-19 caused by SARS-CoV-2 infection a global pandemic. While China experienced a dramatic decline in daily growth rate of COVID-19, multiple importations of new cases from other countries and their related local infections caused a rapid rise. Between March 12 and April 15, we collected nasopharyngeal samples from 109 imported cases from 25 countries and 69 local cases in Guangzhou, China. In order to characterize the transmission patterns and genetic evolution of this virus among different populations, we sequenced the genome of SARS-CoV-2. The imported viral strains were assigned to lineages distributed in Europe (33.0%), America (17.4%), Africa (25.7%), or Southeast/West Asia (23.9%). Importantly, 10 imported cases from Africa formed two novel sub-lineages not identified in global tree previously. A detailed analysis showed that the imported viral strains from Philippines and Pakistan were closely related and within the same sub-lineage, whereas Ethiopia had varied lineages in the African phylogenetic tree. In spite of the diversity of imported SARS-CoV-2, 60 of 69 local infections could be traced back to two specific small lineages imported from Africa. A combined genetic and epidemiological analysis revealed a high-resolution transmission network of the imported SARS-CoV-2 in local communities, which might help inform the public health response and genomic surveillance in other cities and regions. Finally, we observed in-frame deletions on seven loci of SARS-CoV-2 genome, some of which were intra-host mutations, and they exhibited no enrichment on the S protein. Our findings provide new insight into the viral phylodynamics of SARS-CoV-2 and beta coronavirus.