Discovery of orally active SARS-CoV-2 papain-like protease (PLpro) inhibitors (preprint)

Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

Impact of the COVID-19 Pandemic on Malaria Control in Africa: A Preliminary Analysis.

Malaria remains a significant public health concern in Africa, and the emerging coronavirus disease 2019 (COVID-19) pandemic may have negatively impacted malaria control. Here, we conducted a descriptive epidemiological analysis of malaria globally, and preliminarily explored the impact of COVID-19 on the malaria elimination program in regions of Africa (AFR). The present analysis found that there was a vast heterogeneity of incidence of deaths caused by malaria globally in different continents, and the highest malaria burden was observed in AFR. In 2020, there was an obviously increasing trend in the malaria epidemic in AFR, while the other four continents exhibited stable and declining patterns. Historically, malaria has been largely concentrated in high-malaria-burden regions, such as West Africa, and there has been an obvious increasing trend in Nigeria. These data suggest that dynamic changes in the malaria epidemic situation worldwide have primarily originated from AFR, and West Africa has played an important role in the global malaria increase in recent years. Under the coercion of COVID-19, multiple factors have co-driven the increase in malaria in AFR, including insufficient financial investments, a high native malaria burden, weak surveillance systems, limited medical resources, and low socioeconomic development levels. In addition, the shift of medical resources (e.g., health workers and personal protective equipment (PPE), the manufacturing of diagnostic reagents, and drugs) from malaria control to emergency COVID-19 response in the pandemic's early stage caused disruptions, reductions, and delays in pillar malaria control measures, leading to a significant negative impact on malaria control. In particular, a funding shortfall at both the international and domestic levels led to a "significant threat," resulting in vast gaps in access to proven malaria control tools. Although there has been a declining trend in malaria control over time due to COVID-19, the effect still cannot be ignored. Hence, we recommend the implementation of medical and technical resource assistance as a priority strategy to support Africa (West Africa) in order to curb further transmission.

Evolving trend change during the COVID-19 pandemic

Coronavirus disease (COVID-19) has caused unimaginable damage to public health and socio-economic structures worldwide;thus, an epidemiological depiction of the global evolving trends of this disease is necessary. As of March 31, 2022, the number of cases increased gradually over the four waves of the COVID-19 pandemic, indicating the need for continuous countermeasures. The highest total cases per million and total deaths per million were observed in Europe (240,656.542) and South America (2,912.229), despite these developed countries having higher vaccination rates than other continents, such as Africa. In contrast, the lowest of the above two indices were found in undeveloped African countries, which had the lowest number of vaccinations. These data indicate that the COVID-19 pandemic is positively related to the socio-economic development level;meanwhile, the data suggest that the vaccine currently used in these continents cannot completely prevent the spread of COVID-19. Thus, rethinking the feasibility of a single vaccine to control the disease is needed. Although the number of cases in the fourth wave increased exponentially compared to those of the first wave, ~43.1% of deaths were observed during the first wave. This was not only closely linked to multiple factors, including the inadequate preparation for the initial response to the COVID-19 pandemic, the gradual reduction in the severity of additional variants, and the protection conferred by prior infection and/or vaccination, but this also indicated the change in the main driving dynamic in the fourth wave. Moreover, at least 12 variants were observed globally, showing a clear spatiotemporal profile, which provides the best explanation for the presence of the four waves of the pandemic. Furthermore, there was a clear shift in the trend from multiple variants driving the spread of disease in the early stage of the pandemic to a single Omicron lineage predominating in the fourth wave. These data suggest that the Omicron variant has an advantage in transmissibility over other contemporary co-circulating variants, demonstrating that monitoring new variants is key to reducing further spread. We recommend that public health measures, along with vaccination and testing, are continually implemented to stop the COVID-19 pandemic.

Multiple introduced lineages and the single native lineage co-driving the four waves of the COVID-19 pandemic in West Africa

Coronavirus disease 2019 (COVID-19) has become a vast burden on public health and socioeconomics in West Africa, but the epidemic situation is unclear. Therefore, we conducted a retrospective analysis of the positive rate, death rate, and diversity of SARS-CoV-2. As of March 31, 2022, a total of 894,813 cases of COVID-19 have been recorded, with 12,028 deaths, both of which were distributed in all 16 countries. There were four waves of COVID-19 during this period. Most cases were recorded in the second wave, accounting for 34.50% of total cases. These data suggest that although West Africa seems to have experienced a low and relatively slow spread of COVID-19, the epidemic was ongoing, evolving with each COVID-19 global pandemic wave. Most cases and most deaths were both recorded in Nigeria. In contrast, the fewest cases and fewest deaths were reported, respectively, in Liberia and Sierra Leone. However, high death rates were found in countries with low incidence rates. These data suggest that the pandemic in West Africa has so far been heterogeneous, which is closely related to the infrastructure of public health and socioeconomic development (e.g., extreme poverty, GDP per capita, and human development index). At least eight SARS-CoV-2 variants were found, namely, Delta, Omicron, Eta, Alpha, Beta, Kappa, Iota, and Gamma, which showed high diversity, implicating that multiple-lineages from different origins were introduced. Moreover, the Eta variant was initially identified in Nigeria and distributed widely. These data reveal that the COVID-19 pandemic in the continent was co-driven by both multiple introduced lineages and a single native lineage. We suggest enhancing the quarantine measures upon entry at the borders and implementing a genome surveillance strategy to better understand the transmission dynamics of the COVID-19 pandemic in West Africa.

Epidemiological Trends of Coronavirus Disease 2019 in Sierra Leone From March 2020 to October 2021.

Coronavirus disease 2019 (COVID-19), a serious public health challenge the world over, has led to significant health concerns in Sierra Leone. In the present study, epidemic indices, such as the number of cases, positivity rate, reproduction rate (R0), case fatality rate (CFR), age, and sex, were used to characterize the epidemiological trends of COVID-19. As of October 31, 2021, a total of 6,398 cases and 121 related deaths had been confirmed. The total number of COVID-19 reverse transcription polymerase chain reaction (RT-PCR) tests conducted to October 31, 2021, was 249,534, and the average positivity rate was 2.56%. Three waves of COVID-19 were recorded, occurring during weeks 15-46 in 2020 (2,369 cases), week 47 in 2020 to week 16 in 2021 (1,665 cases), and weeks 17-43 in 2021 (2,364 cases), respectively. Remarkably, there was no increase in the numbers of confirmed COVID-19 cases despite rising test numbers throughout the three waves. Moreover, three high R0 values were observed before each wave. The number of positive cases significantly correlated with positive numbers of international arrivals (P < 0.01), deaths (P < 0.01), and the positivity rate of tested samples (P < 0.01). Moreover, all of the deaths occurred during the peak of the three waves. Our results indicate that there was a low level of COVID-19 epidemic in Sierra Leone and that COVID-19's introduction led to local transmission. It is vital to fight against the spread of SARS-CoV-2 from the source of origin by strengthening testing and management of people entering the country. Our findings will provide important clues for expanding sample screening and will contribute to the reasonable allocation of medical resources.

Characteristics of Creutzfeldt-Jakob disease cases reported by surveillance network in China, 2020

Objective: To investigate the incidence, epidemiology and clinical characteristics of Creutzfeldt-Jakob disease (CJD) in China in 2020.

To Adopt CCU Technology or Not? An Evolutionary Game between Local Governments and Coal-Fired Power Plants

Carbon dioxide capture and utilization (CCU) technology is a significant means by which China can achieve its ambitious carbon neutrality goal. It is necessary to explore the behavioral strategies of relevant companies in adopting CCU technology. In this paper, an evolutionary game model is established in order to analyze the interaction process and evolution direction of local governments and coal-fired power plants. We develop a replicator dynamic system and analyze the stability of the system under different conditions. Based on numerical simulation, we analyze the impact of key parameters on the strategies of stakeholders. The simulation results show that the unit prices of hydrogen and carbon dioxide derivatives have the most significant impact: when the unit price of hydrogen decreases to 15.9 RMB/kg or the unit price of carbon dioxide derivatives increases to 3.4 RMB/kg, the evolutionary stabilization strategy of the system changes and power plants shift to adopt CCU technology. The results of this paper suggest that local governments should provide relevant support policies and incentives for CCU technology deployment, as well as focusing on the synergistic development of CCU technology and renewable energy hydrogen production technology.