Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Nature, Journal Year: 2020, Volume and Issue: 581(7807), P. 215 - 220

Published: March 30, 2020

A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide to other countries around the world1-3. Here, better understand initial step of infection at atomic level, we determined crystal structure receptor-binding domain (RBD) spike protein SARS-CoV-2 bound cell receptor ACE2. The overall ACE2-binding mode RBD is nearly identical SARS-CoV RBD, which also uses ACE2 as receptor4. Structural analysis identified residues are essential for binding, majority either conserved or share similar side chain properties with those RBD. Such similarity sequence strongly indicate convergent evolution between RBDs improved binding ACE2, although does not cluster within SARS SARS-related coronaviruses1-3,5. epitopes two antibodies target analysed providing insights into future identification cross-reactive antibodies.

Language: Английский

---

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

BioScience Trends, Journal Year: 2020, Volume and Issue: 14(1), P. 72 - 73

Published: Feb. 18, 2020

The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug of malaria, shown have apparent efficacy acceptable safety against COVID-19 associated pneumonia multicenter clinical trials conducted recommended be included the next version Guidelines Prevention, Diagnosis, Treatment Pneumonia Caused by issued National Health Commission People's Republic China infection larger populations future.

Language: Английский

---

The COVID‐19 epidemic

Tropical Medicine & International Health, Journal Year: 2020, Volume and Issue: 25(3), P. 278 - 280

Published: Feb. 13, 2020

The current outbreak of the novel coronavirus SARS-CoV-2 (coronavirus disease 2019; previously 2019-nCoV), epi-centred in Hubei Province People's Republic China, has spread to many other countries. On 30. January 2020, WHO Emergency Committee declared a global health emergency based on growing case notification rates at Chinese and international locations. detection rate is changing daily can be tracked almost real time website provided by Johns Hopkins University 1 forums. As midst February China bears large burden morbidity mortality, whereas incidence Asian countries, Europe North America remains low so far. Coronaviruses are enveloped, positive single-stranded RNA viruses that infect humans, but also wide range animals. were first described 1966 Tyrell Bynoe, who cultivated from patients with common colds 2. Based their morphology as spherical virions core shell surface projections resembling solar corona, they termed coronaviruses (Latin: corona = crown). Four subfamilies, namely alpha-, beta-, gamma- delta-coronaviruses exist. While alpha- beta-coronaviruses apparently originate mammals, particular bats, delta-viruses pigs birds. genome size varies between 26 kb 32 kb. Among seven subtypes may cause severe fatalities, alpha-coronaviruses asymptomatic or mildly symptomatic infections. belongs B lineage closely related SARS-CoV virus 3, 4. major four structural genes encode nucleocapsid protein (N), spike (S), small membrane (SM) glycoprotein (M) an additional (HE) occurring HCoV-OC43 HKU1 5. 96% identical whole-genome level bat succeeded making its transition animals humans Huanan seafood market Wuhan, China. However, endeavours identify potential intermediate hosts seem have been neglected Wuhan exact route transmission urgently needs clarified. initial clinical sign SARS-CoV-2-related COVID-19 which allowed was pneumonia. More recent reports describe gastrointestinal symptoms infections, especially among young children 6. Observations far suggest mean incubation period five days 7 median 3 (range: 0–24 days) 8. proportion individuals infected remain throughout course infection not yet definitely assessed. In patients, manifestations usually start after less than week, consisting fever, cough, nasal congestion, fatigue signs upper respiratory tract progress dyspnoea chest corresponding pneumonia approximately 75% seen computed tomography admission Pneumonia mostly occurs second third week infection. Prominent viral include decreased oxygen saturation, blood gas deviations, changes visible through X-rays imaging techniques, ground glass abnormalities, patchy consolidation, alveolar exudates interlobular involvement, eventually indicating deterioration. Lymphopenia appears common, inflammatory markers (C-reactive proinflammatory cytokines) elevated. Recent investigations 425 confirmed cases demonstrate epidemic double number affected every each patient spreads 2.2 average (R0) Estimates 2003 reported R0 9. A data-driven analysis early phase estimates 3.58 10. Dense communities risk most vulnerable region certainly Africa, due dense traffic Africa. Very few African countries sufficient appropriate diagnostic capacities obvious challenges exist handle such outbreaks. Indeed, might soon affect identified 13 top-priority (Algeria, Angola, Cote d'Ivoire, Democratic Congo, Ethiopia, Ghana, Kenya, Mauritius, Nigeria, South Tanzania, Uganda, Zambia) either maintain direct links high volume travel studies indicate ≥60 years age higher likely become or, if so, show milder even 7. 13. fatality infections 2.2% (1370/60363; 06:53 PM CET); it 9.6% (774/8096) 11 34.4% (858/2494) MERS-CoV since 2012 12. Like viruses, infects lung epithelial cells using receptor-mediated endocytosis via angiotensin-converting enzyme II (ACE2) entry receptor Artificial intelligence predicts drugs associated AP2-associated kinase (AAK1) disrupting these proteins inhibit into target Baricitinib, used treatment rheumatoid arthritis, AAK1 Janus inhibitor suggested for controlling replication Moreover, one vitro study remdesivir, adenosine analogue acts inhibitor, improved condition 14, 15. Chloroquine, increasing endosomal pH required virus-cell fusion, blocking 15 shown activation p38 mitogen-activated (MAPK), involved HCoV-229E 16. combination antiretroviral lopinavir ritonavir significantly 17 option Further possibilities leronlimab, humanised monoclonal antibody (CCR5 antagonist), galidesivir, nucleoside polymerase both survival benefits several deadly being considered candidates 18. Repurposing available immediate use could improve currently management. Clinical trials presently registered ClinicalTrials.gov focus efficacy immunoglobulins, arbidol hydrochloride combined interferon atomisation, ASC09F+Oseltamivir, plus oseltamivir, ritonavir, mesenchymal stem cell treatment, darunavir cobicistat, hydroxychloroquine, methylprednisolone washed microbiota transplantation 19. Given fragile systems sub-Saharan new re-emerging outbreaks potentially paralyse expense primary healthcare requirements. impact Ebola economy structures still felt later those affected. Effective responses preparedness during emergencies magnitude challenging across lower-middle-income Such situations partly only mitigated supporting existing regional structures.

Language: Английский

---

SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development

Frontiers in Cellular and Infection Microbiology, Journal Year: 2020, Volume and Issue: 10

Published: Nov. 25, 2020

The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to world in many aspects. Effective therapeutic and preventive approaches including drugs vaccines are still unavailable although they development. Comprehensive understandings on life logic SARS-CoV-2 interaction virus with hosts fundamentally important fight against SARS-CoV-2. In this review, we briefly summarized current advances research, epidemic situation epidemiological characteristics caused disease COVID-19. We further discussed biology SARS-CoV-2, origin, evolution, receptor recognition mechanism And particularly, introduced protein structures structure-based therapeutics development antibodies, antiviral compounds, vaccines, indicated limitations perspectives research. wish information provided by review may be helpful global battle infection.

Language: Английский

---

Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2)

Pharmacological Research, Journal Year: 2020, Volume and Issue: 156, P. 104761 - 104761

Published: March 20, 2020

Language: Английский

---

COVID-19 and multiorgan failure: A narrative review on potential mechanisms

Journal of Molecular Histology, Journal Year: 2020, Volume and Issue: 51(6), P. 613 - 628

Published: Oct. 4, 2020

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to disease (COVID-19) pandemic. While the common cold symptoms are observed mild cases, COVID-19 is accompanied by multiorgan failure patients. involvement different organs patients results lengthening hospitalization duration and increasing mortality rate. In this review, we aimed investigate patients, particularly cases. Also, tried define potential underlying mechanisms SARS-CoV2 induced failure. multi-organ dysfunction characterized lung failure, liver kidney injury, cardiovascular disease, as well a wide spectrum hematological abnormalities neurological disorders. most important related direct indirect pathogenic features SARS-CoV2. Although presence angiotensin-converting enzyme 2, receptor lung, heart, kidney, testis, liver, lymphocytes, nervous system was confirmed, there controversial findings about observation RNA these organs. Moreover, organ may be cytokine storm, result increased levels inflammatory mediators, endothelial dysfunction, coagulation abnormalities, infiltration cells into Therefore, further investigations needed detect exact pathogenesis. Since several for clinicians, their knowledge help improve outcomes decrease rate morbidity.

Language: Английский

---

Advances in COVID-19 mRNA vaccine development

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 23, 2022

Abstract To date, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has determined 399,600,607 cases and 5,757,562 deaths worldwide. COVID-19 is a serious threat to human health globally. The World Health Organization (WHO) declared pandemic major public emergency. Vaccination most effective economical intervention for controlling spread of epidemics, consequently saving lives protecting population. Various techniques have been employed in development vaccines. Among these, messenger RNA (mRNA) vaccine drawing increasing attention owing its great application prospects advantages, which include short cycle, easy industrialization, simple production process, flexibility respond new variants, capacity induce better immune response. This review summarizes current knowledge on structural characteristics, antigen design strategies, delivery systems, industrialization potential, quality control, latest clinical trials real-world data mRNA vaccines as well technology. Current challenges future directions preventive infectious diseases are also discussed.

Language: Английский

---

Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells, Journal Year: 2021, Volume and Issue: 10(4), P. 821 - 821

Published: April 6, 2021

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) around 26 32 kilobases, and has been known cause infection a myriad mammalian hosts, such as humans, cats, bats, civets, dogs, camels with varied consequences in terms death debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), found be causative agent disease-19 (COVID-19), shows 88% sequence identity bat-SL-CoVZC45 bat-SL-CoVZXC21, 79% SARS-CoV 50% MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between receptor binding domain (RBD) spike protein (S) SARS-CoV-2 SARS-CoV. During infection, compared displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage S by transmembrane protease serine (TMPRSS2). Following cellular entry, ORF-1a ORF-1ab, located downstream 5′ end + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a pp1ab. These following protease-induced molecular assembly, form functional viral polymerase, also referred replicase. Thereafter, uninterrupted orchestrated replication-transcription events lead synthesis multiple nested sets subgenomic mRNAs (sgRNAs), which are finally translated several accessory proteins participating structure formation various functions virus, assemble encapsulate genomic (gRNA), resulting numerous progenies, eventually exit cell, spread rest body. In this review, we primarily focus on organization, non-structural components, potential prospective targets development therapeutic drugs, convalescent plasm therapy, vaccines tackle infection.

Language: Английский

---

COVID‐19: Virology, biology and novel laboratory diagnosis

The Journal of Gene Medicine, Journal Year: 2020, Volume and Issue: 23(2)

Published: Dec. 11, 2020

Abstract Background At the end of December 2019, a novel coronavirus tentatively named SARS‐CoV‐2 in Wuhan, central city China, was announced by World Health Organization. is an RNA virus that has become major public health concern after outbreak Middle East Respiratory Syndrome‐CoV (MERS‐CoV) and Severe Acute (SARS‐CoV) 2002 2012, respectively. As 29 October 2020, total number COVID‐19 cases had reached over 44 million worldwide, with more than 1.17 confirmed deaths. Discussion infected patients usually present severe viral pneumonia. Similar to SARS‐CoV, enters respiratory tract cells via angiotensin‐converting enzyme receptor 2. The structural proteins play essential role budding particles released from different host cells. To date, approved vaccine or treatment option preventive character avoid courses still not available. Conclusions In study, we provide brief review general biological features CoVs explain pathogenesis, clinical symptoms diagnostic approaches regarding monitoring future infectivity prevent emerging infections.

Language: Английский

---

Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 11, 2021

Abstract The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 exceptionally high level transmissibility extremely broad tissue tropism. However, the underlying molecular mechanism responsible sustaining this degree virulence remains largely unexplored. In article, we review current knowledge crucial information about how attaches on surface host cells through a variety receptors, such as ACE2, neuropilin-1, AXL, antibody–FcγR complexes. We further explain its spike (S) protein undergoes conformational transition from prefusion to postfusion with help proteases like furin, TMPRSS2, cathepsins. then ongoing experimental studies clinical trials antibodies, peptides, or small-molecule compounds anti-SARS-CoV-2 activity, discuss these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce exposure fusion peptide curtail membrane block formation six-helix bundle (6-HB) core. Finally, specter rapidly emerging variants deserves serious broad-spectrum drugs vaccines long-term prevention control COVID-19 future.

Language: Английский

---