Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7818 - 7832

Published: May 31, 2022

The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative discovery and development direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) emerged as a validated target for therapeutics because pivotal role it plays in replication. We describe herein structure-guided design highly potent inhibitors 3CLpro that incorporate their structure novel spirocyclic elements optimizing potency by accessing new chemical space. Inhibitors both MERS-CoV exhibit nM high safety indices have been identified. mechanism action structural determinants associated with binding were established using high-resolution cocrystal structures.

Language: Английский

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Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(4), P. e1011206 - e1011206

Published: April 5, 2023

Investigation of potential hosts the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks spillover and spillback. SARS-CoV-2 has been reported be transmitted from humans various animals after requiring relatively few mutations. There significant interest in describing how virus interacts with mice as they are well adapted human environments, used widely infection models can infected. Structural binding data mouse ACE2 receptor Spike protein newly identified variants needed better understand impact immune system evading mutations present concern (VOC). Previous studies have developed mouse-adapted residues critical for heterologous receptors. Here we report cryo-EM structures bound trimeric ectodomains four different VOC: Beta, Omicron BA.1, BA.2.12.1 BA.4/5. These represent oldest newest known bind receptor. Our high-resolution structural complemented bio-layer interferometry (BLI) assays reveal a requirement combination that enable

Language: Английский

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Roles of host proteases in the entry of SARS-CoV-2

Animal Diseases, Journal Year: 2023, Volume and Issue: 3(1)

Published: April 25, 2023

Abstract The spike protein (S) of SARS-CoV-2 is responsible for viral attachment and entry, thus a major factor host susceptibility, tissue tropism, virulence pathogenicity. S divided with S1 S2 region, the contains receptor-binding domain (RBD), while hydrophobic fusion entry into cell. Numerous proteases have been implicated in activation through various cleavage sites. In this article, we review including furin, trypsin, transmembrane protease serine 2 (TMPRSS2) cathepsins S. Many betacoronaviruses polybasic residues at S1/S2 site which subjected to by furin. facilitates more assessable RBD receptor ACE2, binding triggers further conformational changes exposure S2’ such as type II (TTPRs) TMPRSS2. presence TMPRSS2 on target cells, can utilize direct route envelope cellular membrane. absence TMPRSS2, enter cells via endosomes where multiple cleave successful entry. Additional involved were discussed. This article also includes roles 3C-like inhibitors inhibitory activity against cathepsin L SARS-CoV-2, discussed dual virus replication.

Language: Английский

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SARS-COV-2 Notable Mutations and Variants: A Review Article

Iranian Journal of Public Health, Journal Year: 2022, Volume and Issue: unknown

Published: July 17, 2022

SARS-COV-2 (COVID-19) the virus that caused an epidemic of sever acute respiratory syndrome is what world has been dealing with since Dec 2019. As pandemic continues different variants emerge during mutations have become latest concern, notable examples detected in South Africa, Brazil, and UK. Variants are complicated each one a collection several mutations, all which potential to change unexpected ways. Studying imperative as they can lead increase population immunity. In present study, we reviewed key concerning according WHO tracking Sars-Cov-2 program. Databases were searched through Feb Mar 2022. Overall, 477 studies extracted from databases, among them 165 included 239 COVID-19 43 both variants. At final step data screening 24 associated 31 highlighted information on related for this review article. conclusion, analyses genomic sequence SARS-CoV-2 indicate structural proteins molecules assembly while NSPs biochemical properties possibly cellular functions.

Language: Английский

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Structural understanding of SARS-CoV-2 virus entry to host cells

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Nov. 2, 2023

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health concern associated with millions of fatalities worldwide. Mutant variants virus have further exacerbated COVID-19 mortality and infection rates, emphasizing urgent need for effective preventive strategies. Understanding viral mechanism crucial developing therapeutics vaccines. The entry SARS-CoV-2 into host cells key step in pathway has been targeted drug development. Despite numerous reviews virus, there lack comprehensive focusing on structural aspects entry. In this review, we analyze changes Spike proteins during process, dividing process prebinding, receptor binding, proteolytic cleavage, membrane fusion steps. By understanding atomic-scale details entry, can better target intervention We also examine impacts mutations proteins, including Omicron variant, Structural information provides insights effects guide development Finally, discuss available structure-based approaches Overall, review detailed analysis highlighting its significance vaccines against COVID-19. Therefore, our emphasizes importance combating infection.

Language: Английский

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Analysis of SARS-CoV-2 in Nasopharyngeal Samples from Patients with COVID-19 Illustrates Population Variation and Diverse Phenotypes, Placing the Growth Properties of Variants of Concern in Context with Other Lineages

mSphere, Journal Year: 2022, Volume and Issue: 7(3)

Published: May 2, 2022

SARS-CoV-2 is the causative agent of COVID-19. The virus has spread across planet, causing a global pandemic.

Language: Английский

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Immune response induced by novel coronavirus infection

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: Oct. 25, 2022

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome (SARS-CoV)-2 has been prominent around the world since it was first discovered, affecting more than 100 million people. Although symptoms of most infected patients are not serious, there is still a considerable proportion who need hospitalization and even develop fatal such as cytokine storms, distress so on. Cytokine storm usually described collection clinical manifestations overactivation immune system, which plays an important role in tissue injury multiorgan failure. system healthy individuals composed two interrelated parts, innate adaptive system. Innate immunity body’s line defense against viruses; can quickly perceive viruses through pattern recognition receptors activate related inflammatory pathways to clear pathogens. activated specific antigens mainly CD4+ T cells, CD8+ cells B play different roles viral infection. Here, we discuss response after SARS-CoV-2 In-depth study will help prevent development critical cases aid exploration targeted treatments.

Language: Английский

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Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Dec. 28, 2021

ABSTRACT Investigation of potential hosts the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks spillover and spillback. SARS-CoV-2 has been reported be transmitted from humans various animals after requiring relatively few mutations.[1] There significant interest in describing how virus interacts with mice as they are well adapted human environments, used widely infection models can infected.[2] Structural binding data mouse ACE2 receptor Spike protein newly identified variants needed better understand impact immune system evading mutations present concern (VOC). Previous studies have developed mouse-adapted residues critical for heterologous receptors.[3,4] Here we report cryo-EM structures bound trimeric ectodomains four different VOC: Beta, Omicron BA.1, BA.2.12.1 BA.4/5. These represent oldest newest known bind receptor. Our high-resolution structural complemented bio-layer interferometry (BLI) assays reveal a requirement combination that enable AUTHOR SUMMARY The infect types beyond humans. uses its on surface cells. cells called recognizes. Animals slightly receptors compared Mice research animal live same environments so scientists particularly interested. Understanding proteins binds allows us found new variants. We use high resolution imaging technique cryo-electron microscopy look at where see amino acids. directly individual acids interact Many also increase strength This result suggests may an additional effect influencing it not only but animals.

Language: Английский

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Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

ACS Pharmacology & Translational Science, Journal Year: 2022, Volume and Issue: 6(1), P. 181 - 194

Published: Dec. 28, 2022

The advent of SARS-CoV-2, the causative agent COVID-19, and its worldwide impact on global health, have provided impetus for development effective countermeasures that can be deployed against virus, including vaccines, monoclonal antibodies, direct-acting antivirals (DAAs). Despite these efforts, current paucity DAAs has created an urgent need creation enhanced diversified portfolio broadly acting agents with different mechanisms action effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CLpro), enzyme essential replication, is a validated target discovery therapeutics. In this report, we describe structure-guided utilization cyclopropane moiety in design highly potent inhibitors 3CLpro, SARS-CoV-1 MERS-CoV 3CLpro. High-resolution cocrystal structures were used to identify structural determinants associated binding active site unravel mechanism action. Aldehydes 5c 11c inhibited replication EC50 values 12 11 nM, respectively. Furthermore, corresponding aldehyde bisulfite adducts 5d 11d equipotent 13 safety index (SI) compounds / ranged between 7692 9090. Importantly, aldehydes potently 3CLpro IC50 80 120 70 Likewise, 960 350 nM 790 240 Taken together, studies suggest described herein low cytotoxicity high potency are promising candidates further as broad-spectrum pathogenic coronaviruses.

Language: Английский

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SARS-CoV-2 Seroprevalence Studies in Pets, Spain

Emerging infectious diseases, Journal Year: 2023, Volume and Issue: 29(6)

Published: May 16, 2023

SARS-CoV-2 can infect domestic animals such as cats and dogs. The zoonotic origin of the disease requires surveillance on animals. Seroprevalence studies are useful tools for detecting previous exposure because short period virus shedding in makes detection difficult. We report an extensive serosurvey pets Spain that covered 23 months. included with to SARS-CoV-2-infected persons, random animals, stray study. also evaluated epidemiologic variables human accumulated incidence spatial location. detected neutralizing antibodies 3.59% showed a correlation between COVID-19 humans positivity antibody pets. This study shows more were infected than reports based molecular research, findings highlight need establish preventive measures avoid reverse zoonosis events.

Language: Английский

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