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1.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-463106

RESUMO

Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.

2.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-464595

RESUMO

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a spike-GAG complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar GAG-binding activities but with reduced affinity for DNA topoisomerase may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.

3.
J Environ Manage ; 297: 113335, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34375227

RESUMO

During the last few decades, China's transformation from a low-income country to an emerging economy causes carbon emission to rise extensively. Being the largest carbon emitter, China's continuous economic growth may inevitably cause more carbon emissions in the future. To achieve carbon neutrality targets, the country is striving to promote cleaner technologies. However, to finance these environmentally friendly projects, a well-developed financial system is a pre-requisite. This study examines the role of financial development along with output, financial risk index, renewable energy electricity and human capital on carbon emissions. This study uses updated time series data from 1988 to 2018 for China employing novel econometric approaches, i.e., Narayan and Pop unit root test with structural breaks, Maki cointegration and frequency domain causality test for long, short and medium run causality. The empirical outcome shows that improvement in financial development, renewable energy electricity, and human capital index cause to limit carbon emissions. In contrast, gross domestic product, financial risk index and structural break of 2001 increase carbon emissions. Moreover, structural break year of 2008 and financial development index reduces carbon emissions. The negative association between financial development and carbon emissions supports the positive school of thoughts of financial development that promotes a sustainable environment. This study recommends the promotion of quality human capital and green financial development along with increasing the shares of renewable energy in electricity for achieving China 2030 climate targets of reducing pollution.


Assuntos
Dióxido de Carbono , Carbono , Desenvolvimento Econômico , Eletricidade , Humanos , Energia Renovável
4.
Ann Palliat Med ; 10(7): 7933-7941, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353080

RESUMO

BACKGROUND: Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous units which can affect the individual's physiological and psychological health. Abnormal growth of lipophilic anaerobic bacteria such as Propionibacterium acnes is reported to be a major factor in the development of acne. However, the relationship between skin microorganisms and acne has not been fully elucidated. Our study aimed to explore the microbial differences between patients with acne and healthy controls (HCs). METHODS: The study involved 16 participants diagnosed with acne vulgaris and 5 HCs. We collected skin microbe samples from the cheeks, brow, forehead, neck, chin, or chest of the participants with sterile cotton swabs depending on the location of the acne lesions. Cutaneous microbe samples from the participants were tested by 16s sequencing. RESULTS: Patients with acne showed increased diversity of skin microbiota in their samples. OTU535601 (Lachnospiraceae), OTU4460604 (Clostridiales), OTU3217705 (Moraxellaceae), OTU1066814 (Prevotella), and OTU455671 (Lactococcus garvieae) were the top 5 most abundant species found in patients with acne but were not present in HCs. OTU423327 (Achromobacter), OTU4423360 (Stenotrophomonas), OTU993127 (Porphyromonas), OTU677680 (Prevotella), and OTU269901 (Pseudomonas) were the top 5 most abundant species in HCs but were not found in patients with acne. CONCLUSIONS: The present study has analyzed and compared the diversity and abundance of microorganisms and the characteristics of the main pathogenic bacteria in patients with acne and HCs. Our findings indicate the importance of maintaining the skin's commensal microflora balance with the development of acne vulgaris.


Assuntos
Acne Vulgar , Microbiota , Humanos , Lactococcus , Propionibacterium acnes
5.
J Environ Manage ; 295: 113119, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34216897

RESUMO

To achieve zero carbon or achieving carbon neutrality target is of great importance to many countries around the globe especially post Paris climate agreement. This study, unlike previous studies, evaluates the role of environmental policy, green innovation, composite risk index, and renewable energy R&D in achieving carbon neutrality targets for G7 economies from 1990 to 2019. The results confirmed the validity of the EKC hypothesis for G7 economies. Further, the result shows that environmental policy, green innovation, composite risk index, and renewable energy R&D help control carbon emissions. In contrast, income reveals a positive influence on environmental degradation. Furthermore, bidirectional causality has been reported in environmental policy, composite risk index, green innovation, and the CO2 emissions, while unidirectional causality running from GDP and renewable energy R&D to CO2 emissions. Based on the empirical findings, it is suggested that environmental policies should be strengthened, promote green innovation and renewable energy research and development expenditures, and political stability and institutional quality must be stabilized to lowers sectoral risks that would help a sustainable environment.


Assuntos
Desenvolvimento Econômico , Política Ambiental , Carbono , Dióxido de Carbono , Energia Renovável
6.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-447130

RESUMO

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytophatic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (~16% of predicted hits) active compounds (Efficacy > 30%, IC50 [≤] 15 M). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further analysis identified allosteric binders to host receptor angiotensin-converting enzyme 2, which were able to inhibit the entry of pseudoparticles bearing spike protein of wild type SARS-CoV-2 as well as South African B.1.351 and UK B.1.1.7 variants.

7.
Orthop Surg ; 13(3): 682-691, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33682359

RESUMO

OBJECTIVE: To report a case series of calcaneal fracture-dislocations, which have not been described previously in China, and to provide a systematic review to explore the clinic manifestations, methods for diagnoses, and treatments. METHODS: Between January 2018 and December 2019, 4 patients (4 men; average age, 33.0 ± 16.67 years; range, 15-50 years) were diagnosed with fracture-dislocation of the calcaneus and treated by surgery. We also reviewed published cases and studies of calcaneal fracture-dislocations through the databases of PubMed and Web of Science between January 1977 and December 2019. RESULTS: Between January 2018 and December 2019, 4 cases were identified as calcaneal fracture-dislocations in our hospital. The main clinical manifestations include hindfoot pain, swelling, and deformity. The diagnoses were confirmed via radiographic examination. Two patients underwent open reduction and internal fixation (ORIF) and two were treated with a minimally invasive approach. Diagnosis had been missed in one patient and, consequently, presented with early signs of post-traumatic arthritis, which may require extra subtalar arthrodesis in the future. Two patients were diagnosed inaccurately but achieved satisfactory outcomes through open reduction and internal fixation. The average follow-up period was 9.75 ± 5.19 months. Except for the 1 misdiagnosed patient, the other 3 patients showed functional improvement. Only 23 fracture-dislocations of calcaneus cases were reported in the literature between January 1977 and December 2019. There were 15 Sanders type II fractures (65.22%) and 7 (30.43%) Sanders type III fractures, and there was 1 grade II open calcaneal fracture. Among them, 1 was a medial dislocation and 2 were "joint-elevation" dislocations; the rest of them (20/23, 86.96%) were lateral dislocations. A total of 11 patients (47.83%) exhibited the double-density sign, and varus tilt of the talus was revealed on plain radiographs for 9 patients (39.13%). Increased Bohler's angle was evident in lateral X-ray films for 2 patients (2/23, 8.70%). A total of 21 cases (86.96%) were treated with surgical intervention and achieved satisfactory outcomes. Only 1 patient was treated with external fixation. Another 2 patients were treated conservatively and had poor clinic outcomes. CONCLUSION: Calcaneal fracture-dislocation is a rare injury that is challenging to treat. Clinical manifestations such as fibular tendon dislocation, the double-density sign on profile radiography, and abnormal talar tilt in the distal talofibular joint are important signs that may indicate this rare injury pattern. Timely surgical intervention is essential for satisfactory clinic outcomes. Orthopaedic surgeons should be aware of this uncommon injury to avoid misdiagnosis or inappropriate treatment.

8.
Spectrochim Acta A Mol Biomol Spectrosc ; 248: 119251, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33302218

RESUMO

Fraud in the global food and related products supply chain is becoming increasingly common due to the huge profits associated with this type of criminal activity and yet strategies to detect fraudulent adulteration are still far from robust. Herbal medicines such as Radix Astragali suffer adulteration by the addition of less expensive materials with the objective to increase yield and consequently the profit margin. In this paper, diffuse reflectance mid-infrared Fourier transform spectroscopy (DRIFTS) was used to detect the presence of Jin Quegen in Radix Astragali. 900 fake samples of Radix Astragali produced by 6 different regions were constructed at the levels of 2%, 5%, 10%, 30% and 50% (w/w). DRIFTS data were analyzed using unsupervised classification method such as principal component analysis (PCA), and supervised classification method such as linear discrimination analysis (LDA), K-nearest neighbor (K-NN), linear discrimination analysis combining K-nearest neighbor (LDA-KNN) and partial least squares discriminant analysis (PLS-DA). The results of PCA showed that it was feasible to detect the adulteration of Radix Astragali by the combination of drift technique and chemometrics. PLS-DA obtained the best classification results in all four supervised methods with mean-centralization as the data preprocessing method, the prediction accuracy of PLS-DA model for the six groups of sample ranged from 95.00% to 98.33%. At the same time, LDA-KNN also achieved good classification results, and its correct prediction rate were also between 86.67% and 100.0%. The prediction results confirmed that the combination of DRIFTS technology and chemometrics can distinguish the amount of adulteration present in Radix Astragali. Additionally, the innovative strategy designed can be used to test the fraud of various forms of herbal medicine in other products.


Assuntos
Medicamentos de Ervas Chinesas , Análise de Fourier , Análise dos Mínimos Quadrados , Espectroscopia de Infravermelho com Transformada de Fourier
9.
J Matern Fetal Neonatal Med ; 34(3): 395-402, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31039657

RESUMO

Objectives: In view of the concern expressed about the current references, new references for fetal biparietal diameter and head circumference should be constructed for contemporary local populations.Methods: We conducted a retrospective cross-sectional study in two hospitals in Guangdong, Southern China. Fetal biparietal diameter and head circumference percentiles regression were fitted using Cole's LMS method. The BPD and HC data were then transformed into Z-scores that were calculated using two series of reference equations obtained from two methods: Cole's LMS method and the original "mean and SD method." Each Z-score distribution was presented as the mean and standard deviation. Finally, the sensitivity and specificity of each reference for identifying fetuses <2.5th or >97.5th percentile (based on the observed distribution of Z-scores) were calculated. The misclassified number and Youden's index were listed.Results: A total of 17,974 biparietal diameter and 18,269 head circumference measurements were chosen to establish a reference chart. The LMS method could fit the local population better than the "mean and SD method" as it had a lower number of misclassified fetuses and a higher Youden's index.Conclusion: The Cole's LMS method was able to construct a satisfied reference range of fetal head sizes in Southern China.


Assuntos
Feto , Ultrassonografia Pré-Natal , China , Estudos Transversais , Feminino , Idade Gestacional , Humanos , Gravidez , Valores de Referência , Estudos Retrospectivos
10.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-424413

RESUMO

The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small molecule inhibitors against TMPRSS2. The hits were evaluated in the TMPRSS2 biochemical assay and the SARS-CoV-2 pseudotyped particle (PP) entry assay. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.

11.
Diagnostics (Basel) ; 11(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375089

RESUMO

The water proton spin relaxivity, colloidal stability, and biocompatibility of nanoparticle-based magnetic resonance imaging (MRI) contrast agents depend on the surface-coating ligands. Here, poly(acrylic acid-co-maleic acid) (PAAMA) (Mw = ~3000 amu) is explored as a surface-coating ligand of ultrasmall gadolinium oxide (Gd2O3) nanoparticles. Owing to the numerous carboxylic groups in PAAMA, which allow its strong conjugation with the nanoparticle surfaces and the attraction of abundant water molecules to the nanoparticles, the synthesized PAAMA-coated ultrasmall Gd2O3 nanoparticles (davg = 1.8 nm and aavg = 9.0 nm) exhibit excellent colloidal stability, extremely low cellular toxicity, and a high longitudinal water proton spin relaxivity (r1) of 40.6 s-1mM-1 (r2/r1 = 1.56, where r2 = transverse water proton spin relaxivity), which is approximately 10 times higher than those of commercial molecular contrast agents. The effectiveness of PAAMA-coated ultrasmall Gd2O3 nanoparticles as a T1 MRI contrast agent is confirmed by the high positive contrast enhancements of the in vivo T1 MR images at the 3.0 T MR field.

12.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-366138

RESUMO

The ongoing of coronavirus disease 2019 (COVID-19) pandemic caused by novel SARS-CoV-2 coronavirus, resulting in economic losses and seriously threating the human health in worldwide, highlighting the urgent need of a stabilized, easily produced and effective preventive vaccine. The SARS-COV-2 spike protein receptor binding region (RBD) plays an important role in the process of viral binding receptor angiotensin-converting enzyme 2 (ACE2) and membrane fusion, making it an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticles vaccine candidates, RBD-Ferritin (24-mer), RBD-mi3 (60-mer) and RBD-I53-50 (120-mer), with the application of covalent bond linking by SpyTag-SpyCatcher system. It was demonstrated that the neutralizing capability of sera from mice immunized with three RBD-conjugated nanoparticles adjuvanted with AddaVax or Sigma Systerm Adjuvant (SAS) after each immunization was ~8-to 120-fold greater than monomeric RBD group in SARS-CoV-2 pseudovirus and authentic virus neutralization assay. Most importantly, sera from RBD-conjugated NPs groups more efficiently blocked the binding of RBD to ACE2 or neutralizing antibody in vitro, a further proof of promising immunization effect. Besides, high physical stability and flexibility in assembly consolidated the benefit for rapid scale-up production of vaccine. These results supported that our designed SARS-CoV-2 RBD-conjugated nanoparticle was competitive vaccine candidate and the carrier nanoparticles could be adopted as universal platform for future vaccine development.

13.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20161216

RESUMO

BACKGROUNDThe top priority for the control of COVID-19 pandemic currently is the development of a vaccine. A phase 2 trial conducted to further evaluate the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac). METHODSWe conducted a randomized, double-blind, placebo-controlled trial to evaluate the optimal dose, immunogenicity and safety of the CoronaVac. A total of 600 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine at a dose of 3 g/0.5 mL or 6 g /0.5mL, or placebo on Day 0,14 schedule or Day 0,28 schedule. For safety evaluation, solicited and unsolicited adverse events were collected after each vaccination within 7 days and 28 days, respectively. Blood samples were taken for antibody assay. RESULTSCoronaVac was well tolerated, and no dose-related safety concerns were observed. Most of the adverse reactions fell in the solicited category and were mild in severity. Pain at injection site was the most frequently reported symptoms. No Grade 3 adverse reaction or vaccine related SAEs were reported. CoronaVac showed good immunogenicity with the lower 3 g dose eliciting 92.4% seroconversion under Day 0,14 schedule and 97.4% under Day 0,28 schedule. 28 days after two-dose vaccination, the Nab levels of individual schedules range from 23.8 to 65.4 among different dosage and vaccination schedules. CONCLUSIONSFavorable safety and immunogenicity of CoronaVac was demonstrated on both schedules and both dosages, which support the conduction of phase 3 trial with optimum schedule/dosage per different scenarios.

14.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-225151

RESUMO

Neurological complications are common in patients with COVID-19. While SARS-CoV-2, the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function are not well understood, and experimental models using human brain cells are urgently needed. Here we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found modest numbers of infected neurons and astrocytes, but greater infection of choroid plexus epithelial cells. We optimized a protocol to generate choroid plexus organoids from hiPSCs, which revealed productive SARS-CoV-2 infection that leads to increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our results provide evidence for SARS-CoV-2 neurotropism and support use of hiPSC-derived brain organoids as a platform to investigate the cellular susceptibility, disease mechanisms, and treatment strategies for SARS-CoV-2 infection.

15.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-223578

RESUMO

The recent global pandemic caused by the new coronavirus SARS-CoV-2 presents an urgent need for new therapeutic candidates. While the importance of traditional in silico approaches such as QSAR in such efforts in unquestionable, these models fundamentally rely on structural similarity to infer biological activity and are thus prone to becoming trapped in the very nearby chemical spaces of already known ligands. For novel and unprecedented threats such as COVID-19 much faster and efficient paradigms must be devised to accelerate the identification of new chemical classes for rapid drug development. Here we report the development of a new biological activity-based modeling (BABM) approach that builds on the hypothesis that compounds with similar activity patterns tend to share similar targets or mechanisms of action. In BABM, compound activity profiles established on massive scale across multiple assays are used as signatures to predict compound activity in a new assay or against a new target. We first trained and validated this approach by identifying new antiviral lead candidates for Zika and Ebola based on data from ~0.5 million compounds screened against ~2,000 assays. BABM models were then applied to predict ~300 compounds not previously reported to have activity for SARS-CoV-2, which were then tested in a live virus assay with high (>30%) hit rates. The most potent compounds showed antiviral activities in the nanomolar range. These potent confirmed compounds have the potential to be further developed in novel chemical space into new anti-SARS-CoV-2 therapies. These results demonstrate unprecedented ability using BABM to predict novel structures as chemical leads significantly beyond traditional methods, and its application in rapid drug discovery response in a global public health crisis.

16.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-207019

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C like protease (3CLpro), or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high throughput screening (qHTS) of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CLpro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 28.85 M. Walrycin B (IC50 = 0.26 {micro}M), Hydroxocobalamin (IC50 = 3.29 {micro}M), Suramin sodium (IC50 = 6.5 {micro}M), Z-DEVD-FMK (IC50 = 6.81 {micro}M), LLL-12 (IC50 = 9.84 {micro}M), and Z-FA-FMK (IC50 = 11.39 {micro}M) are the most potent 3CLpro inhibitors. The activities of anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CLpro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients, and as starting points for chemistry optimization for new drug development.

17.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-202549

RESUMO

The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-CoV and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, facilitates the attachment of viral particles to the cell surface to promote cell entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry, and reveals drugs capable of targeting this important step in the viral life cycle.

18.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-197988

RESUMO

While vaccine development will hopefully quell the global pandemic of COVID-19 caused by SARS-CoV-2, small molecule drugs that can effectively control SARS-CoV-2 infection are urgently needed. Here, inhibitors of spike (S) mediated cell entry were identified in a high throughput screen of an approved drugs library with SARS-S and MERS-S pseudotyped particle entry assays. We discovered six compounds (cepharanthine, abemaciclib, osimertinib, trimipramine, colforsin, and ingenol) to be broad spectrum inhibitors for spike-mediated entry. This work should contribute to the development of effective treatments against the initial stage of viral infection, thus reducing viral burden in COVID-19 patients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/197988v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@d60124org.highwire.dtl.DTLVardef@1e5152dorg.highwire.dtl.DTLVardef@d16655org.highwire.dtl.DTLVardef@1957bcc_HPS_FORMAT_FIGEXP M_FIG C_FIG

19.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-135046

RESUMO

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign - named OpenData - with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets. The goal is to support research scientists, clinical investigators and public health officials through open data sharing and analysis tools to expedite the development of SARS-CoV-2 interventions, and to prioritize promising compounds and repurposed drugs for further development in treating COVID-19.

20.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-091520

RESUMO

SARS-CoV-2 is a new type of coronavirus capable of rapid transmission and causing severe clinical symptoms; much of which has unknown biological etiology. It has prompted researchers to rapidly mobilize their efforts towards identifying and developing anti-viral therapeutics and vaccines. Discovering and understanding the virus’ pathways of infection, host-protein interactions, and cytopathic effects will greatly aid in the design of new therapeutics to treat COVID-19. While it is known that chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including inhibiting autophagy, there are also dose-limiting toxicities in patients that make clearly establishing their potential mechanisms-of-action problematic. Therefore, we evaluated a range of other autophagy modulators to identify an alternative autophagy-based drug repurposing opportunity. In this work, we found that 6 of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero-E6 cells with EC50 values ranging from 2.0 to 13 µM and selectivity indices ranging from 1.5 to >10-fold. Immunofluorescence staining for LC3B and LysoTracker dye staining assays in several cell lines indicated their potency and efficacy for inhibiting autophagy correlated with the measurements in the SARS-CoV-2 cytopathic effect assay. Our data suggest that autophagy pathways could be targeted to combat SARS-CoV-2 infections and become an important component of drug combination therapies to improve the treatment outcomes for COVID-19.One Sentence Summary Blocking SARS-CoV-2 cytopathic effects with selective autophagy inhibitors underlying the clinical benefits of chloroquine and hydroxychloroquine.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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