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2.
Indian J Pharmacol ; 52(2): 142-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565603

RESUMO

Knowledge of structural details is very much essential from the drug-design perspective. In the systematic review, we systematically reviewed the structural basis of different target proteins of SARS-corona virus (CoV2) from a viral life cycle and from drug design perspective. We searched four literature (PubMed, EMBASE, NATURE, and Willey online library) databases and one structural database (RCSB.org) with appropriate keywords till April 18, and finally, 26 articles were included in the systematic review. The published literature mainly centered upon the structural details of "spike protein," "main protease/M Pro/3CL pro," "RNA-dependent RNA polymerase," and "nonstructural protein 15 Endoribonuclease" of SARS-CoV-2. However, inhibitor bound structures were very less. We need better structures elucidating the interactions between different targets and their inhibitors which will help us in understanding the atomic level importance of different amino acid residues in the functionality of the target structures. To summarize, we need structures with fine resolution, co-crystallized structures with biologically validated inhibitors, and functional characterization of different target proteins. Some other routes of entry of SARS-CoV-2 are also mentioned (e.g., CD147); however, these findings are not structurally validated. This review may pave way for better understanding of SARS-CoV-2 life cycle from structural biology perspective.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Desenho de Fármacos , Humanos , Pandemias , Pneumonia Viral/virologia
4.
J Phys Chem Lett ; 11(11): 4413-4420, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32406687

RESUMO

Currently, the new coronavirus disease 2019 (COVID-19) is a global pandemic without any well-calibrated treatment. To inactivate the SARS-CoV-2 virus that causes COVID-19, the main protease (Mpro) that performs key biological functions in the virus has been the focus of extensive studies. With the fast-response experimental efforts, the crystal structures of Mpro of the SARS-CoV-2 virus have just become available recently. Herein, we theoretically investigated the mechanism of binding between the Mpro's pocket and various marketed drug molecules being tested in clinics to fight COVID-19 that show promising outcomes. By combining the existing experimental results with our computational ones, we revealed an important ligand binding mechanism of the Mpro, demonstrating that the binding stability of a ligand inside the Mpro pocket can be significantly improved if part of the ligand occupies its so-called "anchor" site. Along with the highly potent drugs and/or molecules (such as nelfinavir) revealed in this study, the newly discovered binding mechanism paves the way for further optimizations and designs of Mpro's inhibitors with a high binding affinity.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Proteínas não Estruturais Virais/química , Betacoronavirus/isolamento & purificação , Sítios de Ligação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Humanos , Ligantes , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Proteínas não Estruturais Virais/metabolismo
5.
Vaccine ; 38(28): 4464-4475, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32418793

RESUMO

The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple Class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.


Assuntos
Desenho de Fármacos , Vacinas contra Ebola/imunologia , Epitopos de Linfócito T/imunologia , Proteínas do Nucleocapsídeo/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas de Subunidades/imunologia , Vacinas Virais , Sequência de Aminoácidos , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Vacinas contra Ebola/química , Epitopos de Linfócito T/química , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Nucleocapsídeo/química , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Vacinas de Subunidades/química , Vacinas Virais/química , Vacinas Virais/imunologia
6.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-32385219

RESUMO

COVID-19 is an emerging infectious disease that has turned into a pandemic. It spreads through droplet transmission of the new coronavirus SARS-CoV-2. It is an RNA virus displaying a spike protein as the major surface protein with significant sequence similarity to SARS-CoV which causes severe acute respiratory syndrome. The receptor binding domain of the spike protein interacts with the human angiotensin converting enzyme 2 and is considered as the antigenic determinant for stimulating an immune response. While multiple candidate vaccines are currently under different stages of development, there are no known therapeutic interventions at the moment. This review describes the key genetic features that are being considered for generating vaccine candidates by employing innovative technologies. It also highlights the global efforts being undertaken to deliver vaccines for COVID-19 through unprecedented international cooperation and future challenges post development.


Assuntos
Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Vacinas Virais/imunologia , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Desenho de Fármacos , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Domínios Proteicos , Subunidades Proteicas , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de DNA , Vacinas Virais/química
7.
Nature ; 581(7808): 252-255, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32415276

Assuntos
Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/imunologia , Desenho de Fármacos , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Vacinas Virais , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Antivirais/química , Azóis/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , China , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Microscopia Crioeletrônica , Cristalização , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Avaliação Pré-Clínica de Medicamentos , Alemanha , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , National Institutes of Health (U.S.)/economia , National Institutes of Health (U.S.)/organização & administração , Compostos Organosselênicos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Inibidores de Proteases/farmacologia , RNA Replicase/antagonistas & inibidores , RNA Replicase/química , RNA Replicase/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Síncrotrons , Fatores de Tempo , Reino Unido , Estados Unidos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/imunologia , Vacinas Virais/química , Vacinas Virais/imunologia
8.
Molecules ; 25(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408547

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of -14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.


Assuntos
Betacoronavirus/enzimologia , Desenho de Fármacos , Serina Endopeptidases/química , Inibidores de Serino Proteinase/química , Bibliotecas de Moléculas Pequenas , Sequência de Aminoácidos , Domínio Catalítico , Simulação por Computador , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos , Gabexato/análogos & derivados , Gabexato/química , Gabexato/metabolismo , Gabexato/farmacologia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/metabolismo , Inibidores de Serino Proteinase/farmacologia
9.
Chem Biol Interact ; 325: 109124, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437694

RESUMO

The prenylated flavonoid icaritin (ICT) is currently undergoing phase 3 clinical trial for the treatment of advanced hepatocellular carcinoma (HCC), based on a solid array of preclinical and clinical data. The antitumor activity originates from the capacity of the drug to modulate several signaling effectors in cancer cells, mainly the estrogen receptor splice variant ERα36, the transcription factors STAT3 and NFκB, and the chemokine receptor CXCR4. Recent studies have implicated additional components, including different microRNAs, the generation of reactive oxygen species and the targeting of sphingosine kinase-1. ICT also engages the RAGE-HMGB1 signaling route and modulates the apoptosis/autophagy crosstalk to promote its anticancer activity. In addition, ICT exerts profound changes on the tumor microenvironment to favor an immune-response. Collectively, these multiple biochemical and cellular characteristics confer to ICT a robust activity profile which can be exploited to treat HCC, as well as other cancers, including glioblastoma and onco-hematological diseases such as chronic myeloid leukemia. This review provides an update of the pharmacological properties of ICT and its metabolic characteristics. It also addresses the design of derivatives, including both natural products and synthetic molecules, such as SNG1153 also in clinical trial. The prenylated flavonoid ICT deserves attention as a multifunctional natural product potentially useful to improve the treatment of advanced hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Flavonoides/química , Flavonoides/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Prenilação , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Desenho de Fármacos , Flavonoides/uso terapêutico , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo
10.
Int J Mol Sci ; 21(9)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32353978

RESUMO

The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.


Assuntos
Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Desenho de Fármacos , Inibidores de Proteases/farmacologia , Bibliotecas de Moléculas Pequenas , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Sítios de Ligação , Domínio Catalítico , Infecções por Coronavirus , Cristalografia por Raios X , Cisteína Endopeptidases/genética , Avaliação Pré-Clínica de Medicamentos , Evolução Molecular , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Pandemias , Pneumonia Viral , Vírus da SARS/enzimologia , Solventes , Termodinâmica , Proteínas não Estruturais Virais/genética
12.
Life Sci ; 250: 117602, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240677

RESUMO

AIMS: Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability. MAIN METHODS: Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces. KEY FINDINGS: Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration. SIGNIFICANCE: Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.


Assuntos
Química Farmacêutica/métodos , Biologia Computacional/métodos , Indóis/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pele/efeitos dos fármacos , Agaricales/metabolismo , Domínio Catalítico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Elétrons , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Quantitativa Estrutura-Atividade , Pigmentação da Pele/efeitos dos fármacos , Tiossemicarbazonas/química , Raios Ultravioleta
13.
Orv Hetil ; 161(14): 523-531, 2020 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-32223419

RESUMO

The one disease - one target - one drug paradigm was an almost dominant principle in drug discovery from the 1960s to the 2000s. The stagnation and even decline in the productivity of drug innovation around the turn of the millennium and beyond, the realization of limitations of the one-target approach, especially in the treatment of multifactorial diseases, have drawn attention considerably to the one disease - multiple target - one drug multi-targeting drug concept. In this review, we outline old and new molecular design strategies and their practical implementation with own and other examples that also demonstrate unique therapeutic and diagnostic values and benefits of the multi-targeting approach. Finally, we point out that the full potential of the multi-targeting concept can emerge through data analytics and association methods (such as artificial intelligence) and system-based approach, preferably by linking it to quantitative systems pharmacology. This new systems pharmacology drug approach may also lead to novel breakthrough drugs, drug combinations and drug repositioning. Orv Hetil. 2020; 161(14): 523-531.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/tendências , Previsões , Humanos
14.
Science ; 368(6497): 1331-1335, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32321856

RESUMO

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.


Assuntos
Antivirais/química , Betacoronavirus/enzimologia , Desenho de Fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Domínio Catalítico , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Estrutura Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Estrutura Terciária de Proteína , Ratos Sprague-Dawley , Testes de Toxicidade , Células Vero
15.
Science ; 368(6492): 779-782, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32277040

RESUMO

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified ß-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.


Assuntos
Betacoronavirus/enzimologia , RNA Replicase/química , RNA Replicase/ultraestrutura , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/ultraestrutura , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacologia , Antivirais/metabolismo , Antivirais/farmacologia , Domínio Catalítico , Microscopia Crioeletrônica , Desenho de Fármacos , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Conformação Proteica em Folha beta , Domínios Proteicos , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
16.
Nat Commun ; 11(1): 2070, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332765

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2.


Assuntos
Betacoronavirus/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/química , Imunoglobulina G/química , Testes de Neutralização , Peptidil Dipeptidase A/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Animais , Betacoronavirus/metabolismo , Ligação Competitiva/efeitos dos fármacos , Reações Cruzadas , Desenho de Fármacos , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulina G/metabolismo , Imunoglobulina G/farmacologia , Técnicas In Vitro , Concentração Inibidora 50 , Fusão de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/farmacocinética , Peptidil Dipeptidase A/farmacologia , Domínios Proteicos/genética , Estabilidade Proteica , Receptores Virais/antagonistas & inibidores , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacocinética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
18.
Nature ; 582(7811): 289-293, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272481

RESUMO

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.


Assuntos
Betacoronavirus/química , Cisteína Endopeptidases/química , Descoberta de Drogas/métodos , Modelos Moleculares , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Células Cultivadas/virologia , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína
19.
ACS Nano ; 14(4): 5143-5147, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32286790

RESUMO

Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Química Computacional , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Simulação de Dinâmica Molecular , Peptídeos , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Humanos , Pandemias , Peptídeos/química , Peptídeos/uso terapêutico , Peptidil Dipeptidase A/efeitos dos fármacos , Conformação Proteica , Conformação Proteica em alfa-Hélice
20.
Science ; 368(6489): 409-412, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32198291

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.


Assuntos
Amidas/química , Amidas/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/química , Amidas/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Pulmão/metabolismo , Camundongos , Modelos Moleculares , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Domínios Proteicos , Multimerização Proteica , Piridonas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
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