Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

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COVID-19 Transmission, Current Treatment, and Future Therapeutic Strategies

Molecular Pharmaceutics, Journal Year: 2021, Volume and Issue: 18(3), P. 754 - 771

Published: Jan. 19, 2021

At the stroke of New Year 2020, COVID-19, a zoonotic disease that would turn into global pandemic, was identified in Chinese city Wuhan. Although unique its transmission and virulence, COVID-19 is similar to diseases, including other SARS variants (e.g., SARS-CoV) MERS, exhibiting severe flu-like symptoms acute respiratory distress. Even at molecular level, many parallels have been between so much virus has named SARS-CoV-2. These similarities provided several opportunities treat patients using clinical approaches were proven be effective against SARS. Importantly, identification how SARS-CoV SARS-CoV-2 access host, replicate, trigger life-threatening pathological conditions revealed repurpose drugs In this article, we first an overview etiology vis-à-vis particularly MERS. Then, summarized characteristics droplets/aerosols emitted by they aid among people. Moreover, discussed mechanisms enable host become more contagious than betacoronaviruses such as SARS-CoV. Further, outlined various are currently being employed diagnose symptomatically clinic. Finally, reviewed technologies develop vaccines attempts classes novel therapeutic approaches.

Language: Английский

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Structural biology of SARS-CoV-2: open the door for novel therapies

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

Published: Jan. 27, 2022

Abstract Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of pandemic disease COVID-19, which so far without efficacious treatment. The discovery therapy reagents for treating COVID-19 are urgently needed, and structures potential drug-target proteins in viral life cycle particularly important. SARS-CoV-2, a member Orthocoronavirinae subfamily containing largest RNA genome, encodes 29 including nonstructural, structural accessory involved adsorption, entry uncoating, nucleic acid replication transcription, assembly release, etc. These individually act as partner machinery or forming complexes with host cellular factors to participate essential physiological activities. This review summarizes representative typically agents that target SARS-CoV-2 some critical pathogenesis, providing insights into mechanisms underlying infection, prevention Indeed, these studies open door COVID therapies, leading ways prevent treat especially, treatment caused by variants imperative.

Language: Английский

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Peptide and peptide-based inhibitors of SARS-CoV-2 entry

Advanced Drug Delivery Reviews, Journal Year: 2020, Volume and Issue: 167, P. 47 - 65

Published: Nov. 13, 2020

To date, no effective vaccines or therapies are available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pandemic agent of disease 2019 (COVID-19). Due to their safety, efficacy and specificity, peptide inhibitors hold great promise for treatment newly emerging viral pathogens. Based on known structures proteins cellular targets, antiviral peptides can be rationally designed optimized. The resulting may highly specific respective targets particular pathogens exert broad activity. Here, we summarize current status inhibiting SARS-CoV-2 entry outline strategies used design targeting ACE2 receptor spike protein its activating proteases furin, transmembrane serine protease (TMPRSS2), cathepsin L. In addition, present approaches related viruses such as SARS-CoV-1 that might implemented inhibition infection.

Language: Английский

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A Comprehensive Review of Viral Characteristics, Transmission, Pathophysiology, Immune Response, and Management of SARS-CoV-2 and COVID-19 as a Basis for Controlling the Pandemic

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Feb. 26, 2021

COVID-19 emerged from China in December 2019 and during 2020 spread to every continent including Antarctica. The coronavirus, SARS-CoV-2, has been identified as the causative pathogen, its stretched capacities of healthcare systems negatively affected global economy. This review provides an update on virus, genome, risks associated with emergence variants, mode transmission, immune response, children elderly, advances made contain, prevent manage disease. Although our knowledge mechanics virus transmission response substantially demystified, concerns over reinfection, susceptibility elderly whether asymptomatic promote remain unanswered. There are also uncertainties about pathophysiology why there variations clinical presentations some patients suffer long lasting symptoms—“ haulers .” To date, no significantly effective curative drugs for COVID-19, especially after failure hydroxychloroquine trials produce positive results. RNA polymerase inhibitor, remdesivir, facilitates recovery severely infected cases but, unlike anti-inflammatory drug, dexamethasone, does not reduce mortality. However, vaccine development witnessed substantial progress several being approved countries around globe.

Language: Английский

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Cell entry by SARS-CoV-2

Trends in Biochemical Sciences, Journal Year: 2021, Volume and Issue: 46(10), P. 848 - 860

Published: June 7, 2021

Both severe acute respiratory syndrome virus 2 (SARS-CoV-2) and SARS-CoV mainly invade human lungs, although increasing evidence shows that SARS-CoV-2 can also infect many other tissues to develop systematic infection multiple organ damage, hijack T cells directly paralyze host immunity.Angiotensin-converting enzyme (ACE2) is the major receptor for a crucial determinant cross-species transmission of virus; establish infections in panel domestic or wild animals via their ACE2 orthologs.Several proteins non-protein molecules have been found interact with S protein serve as potential alternative/auxiliary attachment receptors/coreceptors facilitate entry into specific types cells.Membrane fusion requires two proteolytic events by proteases, S1/S2 boundary harbors polybasic insertion expands spectrum available proteases thus tropism different tissues. Severe invades interacting receptors/coreceptors, well cofactors, its spike (S) further mediates between viral cellular membranes. The membrane protein, angiotensin-converting (ACE2), transmission. In addition, some auxiliary receptors cofactors are involved expand host/tissue SARS-CoV-2. After engagement, required cleave trigger fusogenic activity. Here we discuss recent advances understanding molecular during which will contribute developing vaccines therapeutics. late 2019 novel coronavirus named emerged humans, causes disease (COVID-19) [1.Coronaviridae Study Group International Committee on Taxonomy Viruses species syndrome-related coronavirus: classifying 2019-nCoV naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (2460) Google Scholar, 2.Zhou P. et al.A pneumonia outbreak associated new probable bat origin.Nature. 579: 270-273Crossref (7642) 3.Zhu N. from patients China, 2019.New Engl. J. Med. 382: 727-733Crossref (9884) 4.Wu F. China.Nature. 265-269Crossref (3658) Scholar]. This has rapidly developed worldwide pandemic resulted more than 0.1 billion confirmed cases 23 May 2021, including ~3.5 million deaths (www.who.int/emergencies/diseases/novel-coronavirus-2019). seventh human-infecting (HCoV) identified so far (Box 1), most similar 2002 [4.Wu Scholar,5.Zhong N.S. al.Epidemiology cause (SARS) Guangdong, People's Republic February, 2003.Lancet. 2003; 362: 1353-1358Abstract Full Text PDF (732) However, exhibits higher efficiency (see Glossary) compared HCoVs [6.Madewell Z.J. al.Household SARS-CoV-2: review meta-analysis.JAMA Netw. Open. 3e2031756Crossref (86) Scholar], relatively lower mortality rate Middle East (MERS-CoV) 7.Liu Z. al.The assessment latent period asymptomatic carriers infection.Int. Infect. Dis. 99: 325-327Abstract (12) 8.Zumla A. al.Middle syndrome.Lancet. 2015; 386: 995-1007Abstract (589) Although several candidate being distributed countries, global situation under control. It very urgent promote vaccination among populations effective therapeutics.Box 1Coronaviruses related epidemics/pandemicsCoronaviruses group enveloped viruses whose surface decorated proteins, resulting crown-shaped morphology. genome coronaviruses single-stranded positive-sense RNA an mRNA translation [11.V'Kovski al.Coronavirus biology replication: implications Rev. 19: 155-170Crossref (0) Coronaviruses belong order Nidovirales, family Coronaviridae, classified Orthocoronavirinae Letovirinae subfamilies. All (HCoVs) included subfamily Orthocoronavirinae, divided four genera, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, Deltacoronavirus [9.Siddell S.G. al.Coronaviridae.Intervirology. 1983; 20: 181-189Crossref (55) So far, total seven identified. Among them, 229E, NL63, OC43, HKU1 commonly around world, mild symptoms such common cold fever. three, SARS-CoV, MERS-CoV, SARS-CoV-2, categorized highly pathogenic caused epidemics/pandemics countries.The first 229E reported 1960s (Figure I) [107.Tyrrell D.A. Bynoe M.L. Cultivation type common-cold cultures.Br. 1965; 1: 1467-1470Crossref Scholar,108.Hamre D. Procknow J.J. A isolated tract.Proc. Soc. Exp. Biol. 1966; 121: 190-193Crossref They often detected at same time usually do not lead symptoms. 2004 NL63 was discovered baby bronchiolitis Netherlands [109.van der Hoek L. al.Identification coronavirus.Nat. 2004; 10: 368-373Crossref (1155) year later Hong Kong, China elderly patient [110.Woo P.C. al.Characterization complete sequence coronavirus, HKU1, pneumonia.J. Virol. 2005; 79: 884-895Crossref (920) Since then, this world. case [5.Zhong epidemic spread over 30 countries ended 2003, 8000 infection, almost 800 deaths. MERS-CoV Saudi Arabia 2012 Asian [111.Zaki A.M. al.Isolation man Arabia.New 2012; 367: 1814-1820Crossref (2963) 2500 reported, ~850 died MERS-related disease, highest fatality (~35%) all HCoVs. were Wuhan, [3.Zhu led unprecedented ongoing affects As confirmed, 3.5 death cases. much those but seems be efficient populations. three thought originate animals, potentially natural host, bats [2.Zhou Scholar,112.Hu B. al.Bat origin coronaviruses.Virol. 12: 221Crossref (181) countries. large ~30 000 nt encodes classes proteins: polyproteins, pp1a pp1ab, cleaved 16 non-structural (NSPs) synthesis (and probably functions); structural (the spike, envelope, membrane, nucleocapsid proteins) essential assembly; nine accessory counteract immunity [10.Fehr A.R. Perlman S. Coronaviruses: overview replication pathogenesis.Methods Mol. 1282: 1-23Crossref Scholar,11.V'Kovski Viral step one important processes life cycle, key target process executed envelope recognizes cell allow released cytoplasm [12.Belouzard al.Mechanisms mediated protein.Viruses. 4: 1011-1033Crossref review, summarize functional studies entry, emphasis protein-mediated binding processes, factors coreceptors 1). An average 30–60 trimers protrude virion, distance 15 nm each [13.Yao H. al.Molecular architecture virus.Cell. 183: 730-738Abstract (139) 14.Ke al.Structures distributions intact virions.Nature. 588: 498-502Crossref (170) 15.Turonova al.In situ analysis reveals flexibility hinges.Science. 370: 203-208Crossref (135) Each trimeric ~10 length long helix stalk hinge allows adopt orientations [14.Ke Scholar,15.Turonova typical class I largest machine containing 1200 amino acid residues. During process, undergoes cleavage S1 S2 subunits remain assemble heterodimer 2) [16.Duan glycoprotein biosynthesis, structure, function, antigenicity: design spike-based vaccine immunogens.Front. Immunol. 11576622Crossref (46) Scholar,17.Walls A.C. al.Structure, antigenicity glycoprotein.Cell. 181: 281-292Abstract (2842) subunit N-terminal domain (NTD) C-terminal (CTD), latter responsible termed receptor-binding (RBD) [17.Walls 18.Wrapp al.Cryo-EM structure prefusion conformation.Science. 1260-1263Crossref (19) 19.Wang Q.H. al.Structural basis using ACE2.Cell. 894-904Abstract (890) 20.Lan al.Structure bound receptor.Nature. 581: 215-220Crossref (1531) 21.Shang recognition SARS-CoV-2.Nature. 221-224Crossref (1165) portion consists upstream (UH) region, peptide (FP), heptad repeat 1 (HR1), central (CD), (HR2), transmembrane (TM), cytoplasmic tail (CP) 2A,B). contrast FP located immediate N terminus subunit. Instead, shielded UH therefore second event expose [22.Matsuyama Protease-dependent mechanism coronaviruses.Uirusu. 2011; 61 (article Japanese): 109-116Crossref (1) Scholar,23.Walls al.Tectonic conformational changes fusion.Proc. Natl. Acad. Sci. U. 2017; 114: 11157-11162Crossref (218) Proteolysis S2′ site remove activating capacity triggers irreversible initiate [24.Fan X. post-fusion glycoprotein.Nat. Commun. 11: 3618Crossref (41) 25.Hoffmann M. al.SARS-CoV-2 depends TMPRSS2 blocked clinically proven protease inhibitor.Cell. 271-280Abstract (6278) 26.Cai Y. al.Distinct states protein.Science. 369: 1586-1592Crossref (207) Soon after outbreak, groups promptly 2002–2003 Scholar,25.Hoffmann Scholar] 3). ACE2, carboxypeptidase cleaves polypeptides renin/angiotensin system, cardiac function widely expressed various organs, suggesting [27.Kuba K. al.Multiple functions relevance cardiovascular diseases.Circ. 2013; 77: 301-308Crossref (96) Scholar,28.Yan R. full-length ACE2.Science. 1444-1448Crossref (1720) RBDs share high degree identity (74%) exhibit interaction profiles [19.Wang substitutions residues RBD atomic contacts affinity (~fourfold difference) 3C,D) property may human-to-human Scholar,7.Liu orthologs mammals cats, dogs, pigs, camels, horses, pangolins, bats, indicating SARS-CoV2 likely broad [29.Rodrigues al.Insights modeling.PLoS Comput. 16e1008449Crossref (5) Some closely pangolins Scholar,30.Xiao K.P. SARS-CoV-2-related Malayan pangolins.Nature. 583: 286-289Crossref (208) Two shown wide range bind mediate pseudotyped viruses, S-binding interface displays significant diversity 3E,F) [31.Liu al.Cross-species ACE2.Proc. 2021; 118e2020216118Crossref (2) Scholar,32.Wu al.Broad cat ACE2.Cell Discov. 6: 68Crossref (26) These findings strongly imply experienced spillover adaptation diverse determinants enabled host-jump across intermediate hosts finally allowed humans. Cryogenic electron microscopy (cryo-EM) determined structures conformations, both before Scholar,18.Wrapp Scholar,26.Cai complex [33.Benton D.J. al.Receptor priming fusion.Nature. 327-330Crossref (119) 34.Xu C. al.Conformational dynamics revealed cryo-EM.Sci. Adv. 7eabe5575Crossref (17) 35.Zhou T.Q. without reveal pH-dependent switch endosomal positioning domains.Cell Host Microbe. 28: 867-879Abstract snapshots enable deduction scenario 4). conformations state buried adjacent protomer (closed conformation) exposed access (open (Figures 2C 4A), known Scholar,36.Yuan glycoproteins dynamic domains.Nat. 8: 15092Crossref (342) within synchronized, implying asymmetric interactions receptor. study open transition closed make them accessible 4B) Therefore, 1–3 copies depending conformation individual Scholar,35.Zhou modulates local disrupt core, involves salt bridge contributed residue D614 Progressive dissociation head stalk, facilitates activation proteolysis 4C) Of note, variant harboring D614G substitution Europe mid-2020. mutation makes RB

Language: Английский

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Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases beyond Furin

ACS Infectious Diseases, Journal Year: 2021, Volume and Issue: 7(2), P. 264 - 272

Published: Jan. 12, 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to mediate viral entry into host cells. Cleavage of the S at S1/S2 and/or S2' site(s) is associated with entry, which can occur either cell plasma membrane (early pathway) or endosomal (late pathway), depending on type. Previous studies show that SARS-CoV-2 has a unique insert site be cleaved by furin, appears expand tropism cells suitable protease and receptor expression. Here, we utilize pseudoparticles inhibitors study impact cleavage infectivity. Our results demonstrate essential for early pathway Calu-3 cells, model lung epithelial line, but not late Vero E6 line. was found processed other proteases beyond furin. Using bioinformatic tools, also analyze presence furin in related CoVs offer thoughts origin insertion furin-like SARS-CoV-2.

Language: Английский

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Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity

Journal of Virology, Journal Year: 2022, Volume and Issue: 96(8)

Published: March 28, 2022

SARS-CoV-2, the etiological agent of COVID-19, has so far resulted in >6.1 million deaths worldwide. The spike protein (S) virus directs infection lungs and other tissues by binding angiotensin-converting enzyme 2 (ACE2) receptor.

Language: Английский

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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(4), P. e1009500 - e1009500

Published: April 22, 2021

The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which not observed for other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features coronavirus spike (S) protein, optimize virus towards human respiratory tract. First, S proteins exhibit an intrinsic temperature preference, corresponding with or lower airways. Pseudoviruses bearing (SARS-2-S) were more infectious when produced at 33°C instead 37°C, a property shared protein HCoV-229E, common cold coronavirus. In contrast, MERS-CoV favored accordance preference Next, SARS-2-S-driven entry was efficiently activated by only TMPRSS2, but also TMPRSS13 protease, thus broadening cell tropism SARS-CoV-2. Both proteases proved relevant context authentic replication. appeared effective activator virulent low HCoV-229E virus. Activation SARS-2-S these surface requires processing S1/S2 cleavage loop, both furin recognition motif extended loop length critical. Conversely, deletion mutants significantly increased cathepsin-rich cells. Finally, we demonstrate that D614G mutation increases stability, particularly and, enhances its use cathepsin L pathway. This indicates link between stability usage this alternative route entry. Since properties may promote spread, they potentially explain why spike-G614 variant has replaced early D614 become globally predominant. Collectively, our findings adaptive mechanisms whereby adjusted match protease conditions enhance transmission pathology.

Language: Английский

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SARS-CoV-2 spike engagement of ACE2 primes S2′ site cleavage and fusion initiation

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 119(1)

Published: Dec. 20, 2021

Significance The SARS-CoV-2 spike protein is responsible for host receptor recognition, membrane fusion, and viral infection. Understanding the cellular inhibiting molecular mechanisms of spike-driven entry a research priority in curbing ongoing pandemic preventing future coronavirus outbreaks. Here, we highlight that generation S2′ fragments, proteolytic event occurring within S2 subunit, switch coupled to fusion. Downstream syncytia formation requires presence an cleavage site at arginine 815 but not 685. Hence, processing upon its engagement ACE2 may serve as potential antiviral target against current related strains.

Language: Английский

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