Covid-19 outbreak, ambiguity aversion, and macroeconomic expectations

How will the outbreak of Covid-19 affect people's expectations on the macroeconomy? We conduct an online experiment in China to investigate the relationship between ambiguity aversion, risk aversion, and expectations about the macroeconomy after the onset of Covid-19 which can be considered an uncertainty shock. Our study differs from previous studies as we elicit the individuals' preferences in terms of ambiguity aversion and risk aversion, and test how these preferences drive macroeconomic expectations. We find that ambiguity averse subjects are more pessimistic about the effect of Covid-19 on the economic growth rate. Ambiguity averse subjects are more likely to reduce consumption and expect lower savings in response to the outbreak. More risk taking subjects have more optimistic expectations on the macroeconomy, and they are less likely to reduce consumption, investment, and savings.

Studying the spatiotemporal impacts of socio-demographic and mobility-related factors to predict the spread of COVID-19

Studying the impacts of factors that may vary spatially and temporally as infectious disease progresses is critical for the prediction and intervention of COVID-19. This study aimed to quantitatively assess the spatiotemporal impacts of socio-demographic and mobility-related factors to predict the spread of COVID-19. We designed two different schemes that enhanced temporal and spatial features respectively, and both with the geographically and temporally weighted regression (GTWR) model adopted to consider the heterogeneity and non-stationarity problems, to reveal the spatiotemporal associations between the factors and the spread of COVID-19 pandemic. Results indicate that our two schemes are effective in facilitating the accuracy of predicting the spread of COVID-19. In particular, the temporally enhanced scheme quantifies the impacts of the factors on the temporal spreading trend of the epidemic at the city level. Simultaneously, the spatially enhanced scheme figures out how the spatial variances of the factors determine the spatial distribution of the COVID-19 cases among districts, particularly between the urban area and the surrounding suburbs. Findings provide potential policy implications in terms of dynamic and adaptive anti-epidemic.

Ruxolitinib as an Effective Treatment for Hemophagocytic Lymphohistiocytosis Secondary to SARS-Cov-2 Infection: A Case Report.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. SARS-CoV-2 infection can induce secondary HLH, as described in previous case reports, but diagnosis and treatment are challenging. Case Study: We described an older male patient diagnosed with HLH related to previous SARS-CoV-2 infection. Fever was the only clinical manifestation initially but deterioration in clinical condition and laboratory parameters was observed during hospitalization. He responded poorly to classical therapy but was successfully treated with ruxolitinib. Conclusion: Clinicians should be aware of the possibility of HLH secondary to mild SARS-CoV-2 infection and take timely therapeutic measures to inhibit an inflammatory factor storm. Ruxolitinib is a potential choice for COVID-19 related HLH.

COVID-19 spread prediction using socio-demographic and mobility-related data.

Studying the impacts of factors that may vary spatially and temporally as infectious disease progresses is critical for the prediction and intervention of COVID-19. This study aimed to quantitatively assess the spatiotemporal impacts of socio-demographic and mobility-related factors to predict the spread of COVID-19. We designed two different schemes that enhanced temporal and spatial features respectively, and both with the geographically and temporally weighted regression (GTWR) model adopted to consider the heterogeneity and non-stationarity problems, to reveal the spatiotemporal associations between the factors and the spread of COVID-19 pandemic. Results indicate that our two schemes are effective in facilitating the accuracy of predicting the spread of COVID-19. In particular, the temporally enhanced scheme quantifies the impacts of the factors on the temporal spreading trend of the epidemic at the city level. Simultaneously, the spatially enhanced scheme figures out how the spatial variances of the factors determine the spatial distribution of the COVID-19 cases among districts, particularly between the urban area and the surrounding suburbs. Findings provide potential policy implications in terms of dynamic and adaptive anti-epidemic.

Assessment of community vulnerability during the COVID-19 pandemic: Hong Kong as a case study.

The COVID-19 pandemic continues to threaten global public health. Reliable assessment of community vulnerability is therefore essential to fighting and mitigating the pandemic. This study presents a framework that considers the roles of internal and external factors, including the components of social vulnerability, exposure, and sensitivity, to comprehensively and accurately assess community vulnerability to the pandemic. With respect to internal factors, we summarized the inherent social characteristics of people groups using census data and explored the roles of both overall and four major thematic social vulnerabilities in shaping community infection by COVID-19. We then designed two external factors to characterize exposure and sensitivity and implemented an aggregation by multiplying them with the internal social vulnerability to achieve a comprehensive vulnerability assessment. The role of the estimated vulnerability in shaping community infection was evaluated by statistical and spatial analysis as well as by risk factor classification using defined rules. This case study of Hong Kong demonstrated the value of our framework in vulnerability assessment and revealed the role of vulnerability in shaping community infection by COVID-19.

Cross-regional analysis of the association between human mobility and COVID-19 infection in Southeast Asia during the transitional period of "living with COVID-19”

Background In response to COVID-19, Southeast Asian (SEA) countries had imposed stringent lockdowns and restrictions to mitigate the pandemic ever since 2019. Because of a gradually boosting vaccination rate along with a strong demand for economic recovery, many governments have shifted the intervention strategy from restrictions to "Living with COVID-19” where people gradually resumed their normal activities since the second half of the year 2021. Noticeably, timelines for enacting the loosened strategy varied across Southeast Asian countries, which resulted in different patterns of human mobility across space and time. This thus presents an opportunity to study the relationship between mobility and the number of infection cases across regions, which could provide support for ongoing interventions in terms of effectiveness. Objective This study aimed to investigate the association between human mobility and COVID-19 infections across space and time during the transition period of shifting strategies from restrictions to normal living in Southeast Asia. Our research results have significant implications for evidence-based policymaking at the present of the COVID-19 pandemic and other public health issues. Methods We aggregated weekly average human mobility data derived from the Facebook origin and destination Movement dataset. and weekly average new cases of COVID-19 at the district level from 01-Jun-2021 to 26-Dec-2021 (a total of 30 weeks). We mapped the spatiotemporal dynamics of human mobility and COVID-19 cases across countries in SEA. We further adopted the Geographically and Temporally Weighted Regression model to identify the spatiotemporal variations of the association between human mobility and COVID-19 infections over 30 weeks. Our model also controls for socioeconomic status, vaccination, and stringency of intervention to better identify the impact of human mobility on COVID-19 spread. Results The percentage of districts that presented a statistically significant association between human mobility and COVID-19 infections generally decreased from 96.15% in week 1 to 90.38% in week 30, indicating a gradual disconnection between human mobility and COVID-19 spread. Over the study period, the average coefficients in 7 SEA countries increased, decreased, and finally kept stable. The association between human mobility and COVID-19 spread also presents spatial heterogeneity where higher coefficients were mainly concentrated in districts of Indonesia from week 1 to week 10 (ranging from 0.336 to 0.826), while lower coefficients were mainly located in districts of Vietnam (ranging from 0.044 to 0.130). From week 10 to week 25, higher coefficients were mainly observed in Singapore, Malaysia, Brunei, north Indonesia, and several districts of the Philippines. Despite the association showing a general weakening trend over time, significant positive coefficients were observed in Singapore, Malaysia, western Indonesia, and the Philippines, with the relatively highest coefficients observed in the Philippines in week 30 (ranging from 0.101 to 0.139). Conclusions The loosening interventions in response to COVID-19 in SEA countries during the second half of 2021 led to diverse changes in human mobility over time, which may result in the COVID-19 infection dynamics. This study investigated the association between mobility and infections at the regional level during the special transitional period. Our study has important implications for public policy interventions, especially at the later stage of a public health crisis.

Cross-regional analysis of the association between human mobility and COVID-19 infection in Southeast Asia during the transitional period of "living with COVID-19".

BACKGROUND: In response to COVID-19, Southeast Asian (SEA) countries had imposed stringent lockdowns and restrictions to mitigate the pandemic ever since 2019. Because of a gradually boosting vaccination rate along with a strong demand for economic recovery, many governments have shifted the intervention strategy from restrictions to "Living with COVID-19" where people gradually resumed their normal activities since the second half of the year 2021. Noticeably, timelines for enacting the loosened strategy varied across Southeast Asian countries, which resulted in different patterns of human mobility across space and time. This thus presents an opportunity to study the relationship between mobility and the number of infection cases across regions, which could provide support for ongoing interventions in terms of effectiveness. OBJECTIVE: This study aimed to investigate the association between human mobility and COVID-19 infections across space and time during the transition period of shifting strategies from restrictions to normal living in Southeast Asia. Our research results have significant implications for evidence-based policymaking at the present of the COVID-19 pandemic and other public health issues. METHODS: We aggregated weekly average human mobility data derived from the Facebook origin and destination Movement dataset. and weekly average new cases of COVID-19 at the district level from 01-Jun-2021 to 26-Dec-2021 (a total of 30 weeks). We mapped the spatiotemporal dynamics of human mobility and COVID-19 cases across countries in SEA. We further adopted the Geographically and Temporally Weighted Regression model to identify the spatiotemporal variations of the association between human mobility and COVID-19 infections over 30 weeks. Our model also controls for socioeconomic status, vaccination, and stringency of intervention to better identify the impact of human mobility on COVID-19 spread. RESULTS: The percentage of districts that presented a statistically significant association between human mobility and COVID-19 infections generally decreased from 96.15% in week 1 to 90.38% in week 30, indicating a gradual disconnection between human mobility and COVID-19 spread. Over the study period, the average coefficients in 7 SEA countries increased, decreased, and finally kept stable. The association between human mobility and COVID-19 spread also presents spatial heterogeneity where higher coefficients were mainly concentrated in districts of Indonesia from week 1 to week 10 (ranging from 0.336 to 0.826), while lower coefficients were mainly located in districts of Vietnam (ranging from 0.044 to 0.130). From week 10 to week 25, higher coefficients were mainly observed in Singapore, Malaysia, Brunei, north Indonesia, and several districts of the Philippines. Despite the association showing a general weakening trend over time, significant positive coefficients were observed in Singapore, Malaysia, western Indonesia, and the Philippines, with the relatively highest coefficients observed in the Philippines in week 30 (ranging from 0.101 to 0.139). CONCLUSIONS: The loosening interventions in response to COVID-19 in SEA countries during the second half of 2021 led to diverse changes in human mobility over time, which may result in the COVID-19 infection dynamics. This study investigated the association between mobility and infections at the regional level during the special transitional period. Our study has important implications for public policy interventions, especially at the later stage of a public health crisis.

Active Ingredients of Reduning Injections Maintain High Potency against SARS-CoV-2 Variants.

OBJECTIVE: To investigate the anti-coronavirus potential and the corresponding mechanisms of the two ingredients of Reduning Injection: quercetin and luteolin. METHODS: A pseudovirus system was designed to test the efficacy of quercetin and luteolin to inhibit SARS-CoV-2 infection and the corresponding cellular toxicity. Luteolin was tested for its activities against the pseudoviruses of SARS-CoV-2 and its variants. Virtual screening was performed to predict the binding sites by Autodock Vina 1.1.230 and PyMol. To validate docking results, surface plasmon resonance (SPR) was used to measure the binding affinity of the compounds with various proteins of the coronaviruses. Quercetin and luteolin were further tested for their inhibitory effects on other coronaviruses by indirect immunofluorescence assay on rhabdomyosarcoma cells infected with HCoV-OC43. RESULTS: The inhibition of SARS-CoV-2 pseudovirus by luteolin and quercetin were strongly dose-dependent, with concentration for 50% of maximal effect (EC50) of 8.817 and 52.98 µmol/L, respectively. Their cytotoxicity to BHK21-hACE2 were 177.6 and 405.1 µmol/L, respectively. In addition, luetolin significantly blocked the entry of 4 pseudoviruses of SARS-CoV-2 variants, with EC50 lower than 7 µmol/L. Virtual screening and SPR confirmed that luteolin binds to the S-proteins and quercetin binds to the active center of the 3CLpro, PLpro, and helicase proteins. Quercetin and luteolin showed over 99% inhibition against HCoV-OC43. CONCLUSIONS: The mechanisms were revealed of quercetin and luteolin inhibiting the infection of SARS-CoV-2 and its variants. Reduning Injection is a promising drug for COVID-19.

Dynamics of T follicular helper cells in patients with rheumatic diseases and subsequent antibody responses in a three-dose immunization regimen of CoronaVac.

Given increased acceptance of the CoronaVac, there is an unmet need to assess the safety and immunogenic changes of CoronaVac in patients with rheumatic diseases (RD). Here we comprehensively analysed humoral and cellular responses in patient with RD after a three-dose immunization regimen of CoronaVac. RD patients with stable condition and/or low disease activity (n = 40) or healthy controls (n = 40) were assigned in a 1:1 ratio to receive CoronaVac (Sinovac). The prevalence of anti-receptor binding domain (RBD) antibodies and neutralizing antibodies was similar between healthy control (HC) and RD patients after the second and the third vaccination. However, the titers of anti-RBD IgG and neutralizing antibodies were significantly lower in RD patients compared to HCs (p < 0.05), which was associated with an impaired T follicular helper (Tfh) cell response. Among RD patients, those who generated an antibody response displayed a significantly higher Tfh cells compared to those who failed after the first and the second vaccination (p < 0.05). Interestingly, subjects with a negative serological response displayed a similar Tfh memory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides as their anti-RBD IgG positive counterpart, and all (4/4) of the non-responders in HCs, and 62.5% (5/8) of the non-responders in patients with RD displayed a positive serological response following the third dose. No serious adverse events were observed. In conclusion, our findings support SARS-CoV-2 vaccination in patients with RD with stable and/or low disease activity. The impaired ability in generating vaccine-specific antibodies in patients with RD was associated with a reduction in Tfh cells induction. The window of vaccination times still needs to be explored in future studies. Clinical trial registration: This trial was registered with ChiCTR2100049138.

COVID-19 infection rate but not severity is associated with availability of greenness in the United States.

Human exposure to greenness is associated with COVID-19 prevalence and severity, but most relevant research has focused on the relationships between greenness and COVID-19 infection rates. In contrast, relatively little is known about the associations between greenness and COVID-19 hospitalizations and deaths, which are important for risk assessment, resource allocation, and intervention strategies. Moreover, it is unclear whether greenness could help reduce health inequities by offering more benefits to disadvantaged populations. Here, we estimated the associations between availability of greenness (expressed as population-density-weighted normalized difference vegetation index) and COVID-19 outcomes across the urban-rural continuum gradient in the United States using generalized additive models with a negative binomial distribution. We aggregated individual COVID-19 records at the county level, which includes 3,040 counties for COVID-19 case infection rates, 1,397 counties for case hospitalization rates, and 1,305 counties for case fatality rates. Our area-level ecological study suggests that although availability of greenness shows null relationships with COVID-19 case hospitalization and fatality rates, COVID-19 infection rate is statistically significant and negatively associated with more greenness availability. When performing stratified analyses by different sociodemographic groups, availability of greenness shows stronger negative associations for men than for women, and for adults than for the elderly. This indicates that greenness might have greater health benefits for the former than the latter, and thus has limited effects for ameliorating COVID-19 related inequity. The revealed greenness-COVID-19 links across different space, time and sociodemographic groups provide working hypotheses for the targeted design of nature-based interventions and greening policies to benefit human well-being and reduce health inequity. This has important implications for the post-pandemic recovery and future public health crises.

Social preferences before and after the onset of the COVID-19 pandemic in China

This study compares Chinese people’s trust and trustworthiness, risk attitude, and time preference before and after the onset of the COVID-19 pandemic in China. We compare the preferences of subjects in two online experiments with samples drawn from 31 provinces across mainland China before and after the onset of the pandemic. We test two competing hypotheses regarding trust and trustworthiness. On the one hand, the outbreak as a collective threat could enhance in-group cohesion and cooperation and thus increase trust and trustworthiness. On the other hand, to the extent that people expect their future income to decline, they may become more self-protective and self-controlled, and thus less trusting and trustworthy and more risk averse and patient. Comparing before and after the onset, we found that the subjects increased in trustworthiness. After the onset, trust and trustworthiness (and risk aversion and present bias too) were positively correlated with the COVID-19 prevalence rate in the provinces. Subjects with more pessimistic expectations about income change showed more risk aversion and lower discount rates, supporting the speculation concerning self-control.

Social vulnerability amplifies the disparate impact of mobility on COVID-19 transmissibility across the United States

Although human mobility is considered critical for the spread of the new coronavirus disease (COVID-19) both locally and globally, the extent to which such an association is impacted by social vulnerability remains unclear. Here, using multisource epidemiological and socioeconomic data of US counties, we develop a COVID-19 pandemic vulnerability index (CPVI) to quantify their levels of social vulnerability and examine how social vulnerability moderated the influence of mobility on disease transmissibility (represented by the effective reproduction number, Rt) during the US summer epidemic wave of 2020. We find that counties in the top CPVI quintile suffered almost double in regard to COVID-19 transmission (45.02% days with an Rt higher than 1) from mobility, particularly intracounty mobility, compared to counties in the lowest quintile (21.90%). In contrast, counties in the bottom CPVI quintile were only slightly affected by the level of mobility. As such, a 25% intracounty mobility change was associated with a 15.28% Rt change for counties in the top CPVI quintile, which is eight times the 1.81% Rt change for those in the lowest quintile. These findings suggest the need to account for the vulnerability of communities when making social distancing measures against mobility in the future.

Investigating adolescent mental health of Chinese students during the COVID-19 pandemic: Multicenter cross-sectional comparative investigation.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused significant challenges for adolescent mental health. AIM: To survey adolescent students in China to determine the effects of the COVID-19 pandemic on their mental health. METHODS: A multicenter cross-sectional comparative investigation was conducted in March 2022. We collected demographic information and survey data related to the COVID-19 pandemic. The Patient Health Questionnaire-9 and Generalized Anxiety Disorder Screener scales were used for objective assessment of depression and anxiety. RESULTS: We collected mental health questionnaires from 3184 students. The investigation demonstrated that adolescents most strongly agreed with the following items: Increased time spent with parents, interference with academic performance, and less travel. Conversely, adolescents most strongly disagreed with the following items: Not having to go to school, feeling an increase in homework, and not socializing with people; 34.6% of adolescents were depressed before COVID-19, of which 1.9% were severely depressed. After COVID-19, 26.3% of adolescents were prone to depression, of which 1.4% were severely depressed. 24.4% of adolescents had anxiety before COVID-19, with severe anxiety accounting for 1.6%. After COVID-19, 23.5% of adolescents were prone to anxiety, of which 1.7% had severe anxiety. CONCLUSION: Chinese adolescents in different grades exhibited different psychological characteristics, and their levels of anxiety and depression were improved after the COVID-19 pandemic. Changes in educational management practices since the COVID-19 pandemic may be worth learning from and optimizing in long-term educational planning.

Equality and social determinants of spatial accessibility, availability, and affordability to primary health care in Hong Kong, a descriptive study from the perspective of spatial analysis.

OBJECTIVE: Primary health care (PHC) is widely perceived to be the backbone of health care systems. Since the outbreak of COVID-19, PHC has not only provided primary medical services, but also served as a grassroots network for public health. Our research explored the accessibility, availability, and affordability of primary health care from a spatial perspective, to understand the social determinants affecting access to it in Hong Kong. METHOD: This constitutes a descriptive study from the perspective of spatial analysis. The nearest neighbor method was used to measure the geographic accessibility of PHC based on the road network. The 2SFCA method was used to measure spatial availability and affordability to primary health care, while the SARAR model, Spatial Error model, and Spatial Lag model were then constructed to explain potential factors influencing accessibility and availability of PHC. RESULTS: In terms of accessibility, 95% of residents in Hong Kong can reach a PHC institution within 15 minutes; in terms of availability, 83% of residents can receive PHC service within a month; while in terms of affordability, only 32% of residents can afford PHC services with the support of medical insurance and medical voucher. In Hong Kong, education status and household income show a significant impact on accessibility and availability of PHC. Regions with higher concentrations of residents with post-secondary education receive more PHC resources, while regions with higher concentrations of high-income households show poorer accessibility and poorer availability to PHC. CONCLUSION: The good accessibility and availability of primary health care reflects that the network layout of existing PHC systems in Hong Kong is reasonable and can meet the needs of most residents. No serious gap between social groups further shows equality in resource allocation of PHC in Hong Kong. However, affordability of PHC is not ideal. Indeed, narrowing the gap between availability and affordability is key to fully utilizing the capacity of the PHC system in Hong Kong. The private sector plays an important role in this, but the low coverage of medical insurance in outpatient services exacerbates the crowding of public PHC and underutilization of private PHC. We suggest diverting patients from public to private institutions through medical insurance, medical vouchers, or other ways, to relieve the pressure on the public health system and make full use of existing primary health care in Hong Kong.

A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors.

Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.

A trial of arbidol hydrochloride in adults with COVID-19.

BACKGROUND: To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19. METHODS: This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable. RESULTS: A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%-48.1%; P  = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350-67.410, P < 0.001), as well as hospitalization (median 12.5 days vs. 20.0 days; P < 0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 days vs. 14.5 days; P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. CONCLUSIONS: SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week anas, accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events. TRIAL REGISTRATION: Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term=NCT04260594&draw=2&rank=1.

A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analogue inhibitors

Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5’ end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analogue inhibitors can be bonded to nsp9 and fit into a previously unknown ‘Nuc-pocket’ in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an ‘induce-and-lock’ mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs, but also provide a strategy to design antiviral drugs. Graphical Structural analyses reveal how proteins from SARS-CoV-2 cooperate and use GTP to form the cap on viral mRNA, and how this process is interrupted by nucleotide analogues that serve as antiviral drugs.

Structural insights into Nirmatrelvir (PF-07321332)-3C-like SARS-CoV-2 protease complexation: a ligand Gaussian accelerated molecular dynamics study.

Coronavirus 3C-like protease (3CLpro) is found in SARS-CoV-2 virus, which causes COVID-19. 3CLpro controls virus replication and is a major target for target-based antiviral discovery. As reported by Pfizer, Nirmatrelvir (PF-07321332) is a competitive protein inhibitor and a clinical candidate for orally delivered medication. However, the binding mechanisms between Nirmatrelvir and 3CLpro complex structures remain unknown. This study incorporated ligand Gaussian accelerated molecular dynamics, the one-dimensional and two-dimensional potential of mean force, normal molecular dynamics, and Kramers' rate theory to determine the binding and dissociation rate constants (koff and kon) associated with the binding of the 3CLpro protein to the Nirmatrelvir inhibitor. The proposed approach addresses the challenges in designing small-molecule antiviral drugs.

A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein.

The receptor-binding domain (RBD) in S1 subunit and heptad repeat 1 (HR1) domain in S2 subunit of SARS-CoV-2 spike (S) protein are the targets of neutralizing antibodies (nAbs) and pan-coronavirus (CoV) fusion inhibitory peptides, respectively. However, neither nAb- nor peptide-based drugs can be used orally. In this study, we screened a one-bead-two-compound (OBTC) cyclic γ-AApeptide library against SARS-CoV-2 S protein and identified a hit: S-20 with potent membrane fusion inhibitory activity, but moderate selectivity index (SI). After modification, one derivative, S-20-1, exhibited improved fusion inhibitory activity and SI (>1000). S-20-1 could effectively inhibit infection by pseudotyped and authentic SARS-CoV-2 and pseudotyped variants of concern (VOCs), including B.1.617.2 (Delta) and B.1.1.529 (Omicron), as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It could also inhibit infection of a pseudotyped SARS-related coronavirus WIV1 (SARSr-CoV-WIV1) from bats. Intranasal application of S-20-1 to mice before or after challenge with HCoV-OC43 or SARS-CoV-2 provided significant protection from infection. Importantly, S-20-1 was highly resistant to proteolytic degradation, had long half-life, and possessed favorable oral bioavailability. Mechanistic studies suggest that S-20-1 binds with high affinity to RBD in S1 and HR1 domain in S2 of SARS-CoV-2 S protein. Thus, with its pan-CoV fusion and entry inhibitory activity by targeting two sites in S protein, desirable half-life, and promising oral bioavailability, S-20-1 is a potential candidate for further development as a novel therapeutic and prophylactic drug against infection by SARS-CoV-2 and its variants, as well as future emerging and reemerging CoVs.

Alveolar macrophages: Achilles' heel of SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic has caused more than 6.3 million deaths to date. Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccines and neutralizing antibodies are in the gloom due to persistent viral mutations and antiviral compounds face challenges of specificity and safety. In addition, vaccines are unable to treat already-infected individuals, and antiviral drugs cannot be used prophylactically. Therefore, exploration of unconventional strategies to curb the current pandemic is highly urgent. Alveolar macrophages (AMs) residing on the surface of alveoli are the first immune cells that dispose of alveoli-invading viruses. Our findings demonstrate that M1 AMs have an acidic endosomal pH, thus favoring SARS-CoV-2 to leave endosomes and release into the cytosol where the virus initiates replication; in contrast, M2 AMs have an increased endosomal pH, which dampens the viral escape and facilitates delivery of the virus for lysosomal degradation. In this review, we propose that AMs are the Achilles' heel of SARS-CoV-2 infection and that modulation of the endosomal pH of AMs has the potential to eliminate invaded SARS-CoV-2; the same strategy might also be suitable for other lethal respiratory viruses.