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1.
Ann N Y Acad Sci ; 1510(1): 79-99, 2022 04.
Article in English | MEDLINE | ID: covidwho-1822055

ABSTRACT

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.


Subject(s)
Proteasome Endopeptidase Complex , Ubiquitin , Autophagy/physiology , Humans , Organelles , Proteasome Endopeptidase Complex/metabolism , Proteins/metabolism , Proteolysis , Ubiquitin/metabolism
2.
Sustainability ; 14(7):3753, 2022.
Article in English | MDPI | ID: covidwho-1762758

ABSTRACT

The outbreak of COVID-19 added further stress to individuals' work life, and employability may be especially important to help individuals to pursue sustainable career success in such a context. However, previous studies that examined the impact and the mechanisms of employability on sustainable career success are lacking, especially in the context of pandemic threat. Based on conservation of resource theory (COR), the current study aims to explore whether and how employability, as an important resource, reduced work-related emotional exhaustion and increased work engagement during the COVID-19 pandemic. We expected that self-perceived employability would reduce emotional exhaustion and increase work engagement. We further expected that coping strategy mediated the effect of self-perceived employability on emotional exhaustion, and career commitment mediated its effect on work engagement. Data were collected via a national survey in China among a sample of 4990 human resource practitioners from October to December 2020 amid the COVID-19 outbreak. The proposed model was tested with structural equation modelling. Results supported the proposed model. Self-perceived employability reduced emotional exhaustion and to a larger extent, increases work engagement. The two mediating effects were of partial mediation. The implications of the results for theory and practice are discussed.

3.
ACS Med Chem Lett ; 12(11): 1838-1844, 2021 Nov 11.
Article in English | MEDLINE | ID: covidwho-1507014

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has stimulated the search for effective drugs for its prevention and treatment. Natural products are an important source for new drug discovery. Here, we report that, NK007(S,R), a tylophorine malate, displays high antiviral activity against SARS-CoV-2 with an EC50 0.03 µM in vitro, which is substantially lower than that of remdesivir (EC50: 0.8 µM in vitro), the only authorized drug to date. The histopathological research revealed that NK007(S,R) (5 mg/kg/dose) displayed a protection effect in lung injury induced by SARS-CoV-2, which is better than remdesivir (25 mg/kg/dose). We also prepared two nanosized preparations of NK007(S,R), which also showed good efficacy (EC50: NP-NK007, 0.007 µM in vitro; LP-NK007, 0.014 µM in vitro). Our findings suggest that tylophora alkaloids, isolated from the traditional Chinese medicine Cynanchum komarovii AL, offer a new skeleton for the development of anticoronavirus drug candidate.

4.
Nat Commun ; 12(1): 5000, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361637

ABSTRACT

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.


Subject(s)
Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/drug effects , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Epitopes , Female , HEK293 Cells , Haplorhini , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Pandemics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Vero Cells , Virus Activation
5.
Preprint in English | bioRxiv | ID: ppbiorxiv-439088

ABSTRACT

Angiotensin-converting enzyme-2 (ACE2) has been recognized as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cells while bats has been suspected as natural host of SARS-CoV-2. However, the detail of intermediate host or the route of transmission of SARS-CoV-2 is still unclear. In this study, we analyze the conservation of ACE2 gene in 11 laboratory and wild animals that live in close proximity either with Bats or human and further investigated its RNA and protein expression pattern in wild bats, mice and tree shrew. We verified that the wild-bats and mice were belonged to Hipposideros pomona and Rattus norvegicus, respectively. ACE2 gene is highly conserved among all 11 animals species at the DNA level. Phylogenetic analysis based on the ACE2 nucleotide sequences revealed that wild bat and Tree shrew were forming a cluster close to human. We further report that ACE2 RNA expression pattern is highly species-specific in different tissues of different animals. Most notably, we found that the expression pattern of ACE2 RNA and protein are very different in each animal species. In summary, our results suggested that ACE2 gene is highly conserved among all 11 animals species. However, different relative expression pattern of ACE2 RNA and protein in each animal species is interesting. Further research is needed to clarify the possible connection between different relative expression pattern of ACE2 RNA and protein in different laboratory and wild animal species and the susceptibility to SARS-CoV-2 infection.

6.
J Biomol Struct Dyn ; : 1-16, 2021 Mar 09.
Article in English | MEDLINE | ID: covidwho-1123184

ABSTRACT

A novel acute viral pneumonia induced by SARS-CoV-2 exploded at the end of 2019, causing a severe medical and economic crisis. For developing specific pharmacotherapy against SARS-CoV-2, an in silico virtual screening was developed for the available in-house molecules. The conserved domain analysis was performed to identify the highly conserved and exposed amino acid regions in the SARS-CoV-2-S RBD sites. The Protein-Protein interaction analyses demonstrated the higher affinity between the SARS-CoV-2-S and ACE2 due to varieties of significant interactions between them. The computational alanine scanning mutation study has recognized the highly stabilized amino acids in the SARS-CoV-2-S RBD/ACE2 complex. The cumulative sequence investigations have inferred that Lys417, Phe486, Asn487, Tyr489, and Gln493 are perhaps the iconic target amino acids to develop a drug molecule or vaccine against SARS-CoV-2 infection. Most of the selected compounds include luteolin, zhebeirine, 3-dehydroverticine, embelin, andrographolide, ophiopogonin D, crocin-1, sprengerinin A, B, C, peimine, etc. were exhibited distinguish drug actions through the strong hydrogen bonding with the hot spots of the RBD. Besides, the 100 ns molecular dynamics simulation and free energy binding analysis showed the significant efficacy of luteolin to inhibit the infection of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

7.
Nucleic Acids Res ; 49(7): e37, 2021 04 19.
Article in English | MEDLINE | ID: covidwho-1066376

ABSTRACT

Multiple driver genes in individual patient samples may cause resistance to individual drugs in precision medicine. However, current computational methods have not studied how to fill the gap between personalized driver gene identification and combinatorial drug discovery for individual patients. Here, we developed a novel structural network controllability-based personalized driver genes and combinatorial drug identification algorithm (CPGD), aiming to identify combinatorial drugs for an individual patient by targeting personalized driver genes from network controllability perspective. On two benchmark disease datasets (i.e. breast cancer and lung cancer datasets), performance of CPGD is superior to that of other state-of-the-art driver gene-focus methods in terms of discovery rate among prior-known clinical efficacious combinatorial drugs. Especially on breast cancer dataset, CPGD evaluated synergistic effect of pairwise drug combinations by measuring synergistic effect of their corresponding personalized driver gene modules, which are affected by a given targeting personalized driver gene set of drugs. The results showed that CPGD performs better than existing synergistic combinatorial strategies in identifying clinical efficacious paired combinatorial drugs. Furthermore, CPGD enhanced cancer subtyping by computationally providing personalized side effect signatures for individual patients. In addition, CPGD identified 90 drug combinations candidates from SARS-COV2 dataset as potential drug repurposing candidates for recently spreading COVID-19.


Subject(s)
Algorithms , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drug Therapy, Combination , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Precision Medicine/methods , Breast Neoplasms/classification , COVID-19/drug therapy , COVID-19/genetics , Datasets as Topic , Drug Repositioning , Drug Synergism , Drug-Related Side Effects and Adverse Reactions , Gene Expression Regulation, Neoplastic/genetics , Genes, Neoplasm/genetics , Humans , Risk Assessment , Workflow
8.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-4098

ABSTRACT

A review. Since Sept., 2019, COVID-19 spreads all over 26 countries, and more than 70 000 people got infected till Feb. 22th, 2020. COVID-19 has strong infectivity and can result in acute respiratory distress syndrome and multiple organ failure. These severe complications are believed to be the consequence of cytokine storm caused by the virus infection. In the "diagnosis and treatment of novel coronavirus pneumonia", glucocorticoid is recommended as the immunosuppressive agents to prevent acute immune reaction. But the usage of glucocorticoid may bring risks such as superinfection, prolonged course of disease or severe residual effects. Traditional Chinese Medicine might have advantages in the moderation of immune system. Actually, Traditional Chinese Medicine is now applied in the treatment of COVID-19 clin., and exhibits excellent therapeutic effects. In this review, the potential usage of Traditional Chinese drugs or Traditional prescriptions in inhibiting cytokine storm and acute lung injury are analyzed, which would be an effective strategy for the treatment of COVID-19.

9.
Chin. Trad. Herbal Drugs ; 6(51): 1375-1385, 20200328.
Article in Chinese | WHO COVID, ELSEVIER | ID: covidwho-380619

ABSTRACT

At the end of December, 2019, a novel coronavirus disease (COVID-19) outbreak was found in China. COVID-19 spreads all over 268 countries, and more than 70 000 people got infected till February 23th, 2020. COVID-19 can result in acute respiratory distress syndrome and multiple organ failure due to its strong infectivity and extensive spread. These severe complications are believed to be the consequence of cytokine storm caused by the virus infection. In the “Diagnosis and treatment of novel coronavirus pneumonia”, glucocorticoid is recommended as the immunosuppressive agents to prevent acute immune reaction in critical patients. However, the usage of glucocorticoid may bring severe residual effects such as superinfection risks, prolonged course of disease. Traditional Chinese medicine might have advantages in the moderation of immune system. Actually, TCM is now applied in the treatment of COVID-19 clinically, and exhibits excellent therapeutic effects. In this review, the potential usage of TCM or traditional prescriptions in inhibiting cytokine storm and treating in acute lung injury were analyzed, which would be an effective strategy for the treatment of COVID-19.

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