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1.
Methods Mol Biol ; 2225: 25-38, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108655

RESUMO

Various systems exist for the robust production of recombinant proteins. However, only a few systems are optimal for human vaccine protein production. Plant-based transient protein expression systems offer an advantageous alternative to costly mammalian cell culture-based systems and can perform posttranslational modifications due to the presence of an endomembrane system that is largely similar to that of the animal cell. Technological advances in expression vectors for transient expression in the last two decades have produced new plant expression systems with the flexibility and speed that cannot be matched by those based on mammalian or insect cell culture. The rapid and high-level protein production capability of transient expression systems makes them the optimal system to quickly and versatilely develop and produce vaccines against viruses such as 2019-nCoV that have sudden and unpredictable outbreaks. Here, expression of antiviral subunit vaccines in Nicotiana benthamiana plants via transient expression is demonstrated.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Plantas/imunologia , Pneumonia Viral/prevenção & controle , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/biossíntese , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Vetores Genéticos , Humanos , Plantas/genética , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 244: 118825, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32866803

RESUMO

Novel antiviral active molecule 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl)acetamide has been synthesised and characterized by FT-IR and FT-Raman spectra. The equilibrium geometry, natural bond orbital calculations and vibrational assignments have been carried out using density functional B3LYP method with the 6-311G++(d,p) basis set. The complete vibrational assignments for all the vibrational modes have been supported by normal coordinate analysis, force constants and potential energy distributions. A detailed analysis of the intermolecular interactions has been performed based on the Hirshfeld surfaces. Drug likeness has been carried out based on Lipinski's rule and the absorption, distribution, metabolism, excretion and toxicity of the title molecule has been calculated. Antiviral potency of 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro-phenyl) acetamide has been investigated by docking against SARS-CoV-2 protein. The optimized geometry shows near-planarity between the phenyl ring and the pyrimidine ring. Differences in the geometries due to the substitution of the most electronegative fluorine atom and intermolecular contacts due to amino pyrimidine were analyzed. NBO analysis reveals the formation of two strong stable hydrogen bonded N-H···N intermolecular interactions and weak intramolecular interactions C-H···O and N-H···O. The Hirshfeld surfaces and consequently the 2D-fingerprint confirm the nature of intermolecular interactions and their quantitative contributions towards the crystal packing. The red shift in N-H stretching frequency exposed from IR substantiate the formation of N-H···N intermolecular hydrogen bond. Drug likeness and absorption, distribution, metabolism, excretion and toxicity properties analysis gives an idea about the pharmacokinetic properties of the title molecule. The binding energy -8.7 kcal/mol of the nonbonding interaction present a clear view that 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl) acetamide can irreversibly interact with SARS-CoV-2 protease.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacocinética , Betacoronavirus/enzimologia , Cristalografia por Raios X , Cisteína Endopeptidases , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Dinâmica não Linear , Inibidores de Proteases/farmacocinética , Conformação Proteica , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica , Vibração
3.
Ars pharm ; 61(4): 253-257, oct.-dic. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193586

RESUMO

INTRODUCCIÓN: La Enfermedad por coronavirus 2019 (COVID-19) causada por el virus SARS-CoV-2, con característica de infectar el tracto respiratorio causando un síndrome respiratorio agudo como paso inicial para ingresar a la célula huésped el virus usa los receptores ACE II y la proteína transmembrana TMPRSS2 para causar la infección, Por lo que se ha descrito diferentes tipos de fármacos para realizar su inhibición en la adhesión del paso inicial. METODOLOGÍA: Revisión no sistemática de artículos con la ayuda de palabras clave preestablecidas. RESULTADOS: En esta revisión presentaremos fármacos que inhiben este tipo de receptor, por lo tanto, estos medicamentos podrían considerarse candidatos potenciales para mitigar la propagación del SARS-CoV-2


INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus with characteristic of infecting the respiratory tract, causing severe acute respiratory syndrome. The virus uses the ACE II receptors and the transmembrane protein TMPRSS2 initial step to enter the host cell, this contribution described different types of drug, to perform its inhibition in initial step adhesion. METHODOLOGY: Non-systematic review of articles with the help of preset keywords. RESULTS: In this review we will present drugs that inhibitors of this type of receptor therefore these drugs could be considered potential candidates to mitigate the spread of SARS-CoV-2


Assuntos
Humanos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Serina Endopeptidases/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores de Serino Proteinase/farmacologia , Serina Endopeptidases/farmacologia
4.
Pan Afr Med J ; 35(Suppl 2): 134, 2020.
Artigo em Francês | MEDLINE | ID: mdl-33193949

RESUMO

Hydroxychloroquine is an agent used as a treatment but also considered as a prophylaxis for SARS-CoV-2 infection. We report the case of a patient who developed COVID-19 while on hydroxychloroquine for mixed connectivitis associated with spondyloarthritis. Although more work is needed before any conclusions can be drawn, this raises questions about the protective role of this drug against infection. Are they really protected against COVID-19 or will they develop pauci-symptomatic forms?


Assuntos
Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Etanercepte/uso terapêutico , Hidroxicloroquina/uso terapêutico , Doença Mista do Tecido Conjuntivo/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Dermatopatias Virais/etiologia , Espondiloartropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Urticária/etiologia , Antirreumáticos/efeitos adversos , Infecções por Coronavirus/complicações , Suscetibilidade a Doenças , Etanercepte/efeitos adversos , Humanos , Masculino , Doença Mista do Tecido Conjuntivo/complicações , Pandemias , Pneumonia Viral/complicações , Espondiloartropatias/complicações , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto Jovem
5.
Clin Sci (Lond) ; 134(21): 2851-2871, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33146371

RESUMO

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Receptores Virais/metabolismo , Internalização do Vírus , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Conformação Proteica , Receptores Virais/química , Relação Estrutura-Atividade
6.
Biomed Pharmacother ; 131: 110738, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33152914

RESUMO

The novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be considered as the most important current global issue, as it has caused the novel coronavirus disease (COVID-19) pandemic, which has resulted in high mortality and morbidity rates all around the world. Although scientists are trying to discover novel therapies and develop and evaluate various previous treatments, at the time of writing this paper, there was no definite therapy and vaccine for COVID-19. So, as COVID-19 has called ideas for treatment, controlling, and diagnosis, we discussed the application of Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 (CRISPR/Cas13) as a treatment of COVID-19, which received less attention compared with other potential therapeutic options.


Assuntos
Betacoronavirus/genética , Sistemas CRISPR-Cas , Infecções por Coronavirus/terapia , Edição de Genes , Terapia Genética/métodos , Pneumonia Viral/terapia , RNA Viral/genética , Betacoronavirus/efeitos dos fármacos , Proteínas Associadas a CRISPR/farmacologia , Sequência Conservada , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Genoma Viral , Humanos , Pandemias , Pneumonia Viral/genética , RNA Guia/genética , RNA Viral/antagonistas & inibidores
7.
Int J Med Sci ; 17(18): 3125-3145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173434

RESUMO

The use of multipronged measures, including traditional Chinese medicine (TCM), has greatly increased in response to the COVID-19 pandemic, and we found the use of TCM and is positively correlated with the regional cure rate in China (R=0.77, P<10-5). We analyzed 185 commonly administered TCM recipes comprised of 210 herbs nationwide to reveal mechanistic insight. Eight out of the 10 most commonly used herbs showed anti-coronavirus potential by intersecting with COVID-19 targets. Intriguingly, 17 compounds from the 5 most commonly used herbs were revealed to have direct anti-SARS-CoV-2 potential by docking with the two core structures [CoV spike (S) glycoprotein (6SVB) and CoV 3CL hydrolase (6LU7)]. Seven reported COVID-19 drugs served as positive controls; among them, retionavir (-7.828 kcal/mol) and remdesivir (-8.738 kcal/mol) performed best with 6VSB and 6LU7, respectively. The top candidate was madreselvin B (6SVB: -8.588 kcal/mol and 6LU7: -9.017 kcal/mol), an appreciable component of Flos Lonicerae. Eighty-six compounds from 22 unlisted herbs were further identified among 2,042 natural compounds, completing our arsenal for TCM formulations. The mechanisms have been implicated as multifactorial, including activation of immunoregulation (Th2, PPAR and IL10), suppression of acute inflammatory responses (IL-6, IL-1α/ß, TNF, COX2/1, etc.), enhancement of antioxidative activity (CAT and SOD1), and modulation of apoptosis (inhibited CASP3). It is of interest to understand the biological mechanisms of TCM recipes. We then analyzed 18 representative remedies based on molecular targets associated with 14 medical conditions over the disease course, e.g., pyrexia, coughing, asthenia, lymphopenia, cytokine storm, etc. The significant level of coherence (SLC) revealed, in part, the potential uses and properties of corresponding TCMs. Thus, herbal plants coordinate to combat COVID-19 in multiple dimensions, casting a light of hope before effective vaccines are developed.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Fitoterapia/métodos , Pneumonia Viral/tratamento farmacológico , Algoritmos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Desenvolvimento de Medicamentos , Medicamentos de Ervas Chinesas/classificação , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Pandemias , Fitoterapia/classificação , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
8.
PLoS One ; 15(11): e0241543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33180803

RESUMO

BACKGROUND: The outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS-CoV-2. METHODS AND FINDINGS: We perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we found that 3 of the drugs fulfils the criterions well among which the antiretroviral drug Amprenavir (DrugBank ID-DB00701) would probably be the most effective drug based on the selected criterions. CONCLUSIONS: Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID-19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.


Assuntos
Betacoronavirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Algoritmos , Teorema de Bayes , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico
10.
Clin Sci (Lond) ; 134(21): 2791-2805, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33135725

RESUMO

Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Nefropatias/enzimologia , Rim/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Receptores Virais/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/virologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Diabetes Mellitus/enzimologia , Diabetes Mellitus/fisiopatologia , História do Século XXI , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Pandemias , Peptidil Dipeptidase A/história , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/virologia , Receptores Virais/história
12.
Trials ; 21(1): 906, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33138848

RESUMO

OBJECTIVES: - To describe the evolution of the SARS-CoV-2 salivary viral load of patients infected with Covid-19, performing 7 days of tri-daily mouthwashes with and without antivirals. - To compare the evolution of the SARS-CoV-2 nasal and salivary viral load according to the presence or absence of antivirals in the mouthwash. TRIAL DESIGN: This is a multi-center, randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: Inclusion criteria - Age: 18-85 years old - Clinical diagnosis of Covid-19 infection - Clinical signs have been present for less than 8 days - Virological confirmation - Understanding and acceptance of the trial - Written agreement to participate in the trial Exclusion criteria - Pregnancy, breastfeeding, inability to comply with protocol, lack of written agreement - Patients using mouthwash on a regular basis (more than once a week) - Patient at risk of infectious endocarditis - Patients unable to answer questions - Uncooperative patient The clinical trial is being conducted with the collaboration of three French hospital centers: Hospital Center Emile Roux (Le Puy en Velay, France), Clinic of the Protestant Infirmary (Lyon, France) and Intercommunal Hospital Center (Mont de Marsan, France). INTERVENTION AND COMPARATOR: Eligible participants will be allocated to one of the two study groups. Intervention group: patients perform a tri-daily mouthwash with mouthwash containing antivirals (ß-cyclodextrin and Citrox®) for a period of 7 days. CONTROL GROUP: patients perform a tri-daily mouthwash with a placebo mouthwash for a period of 7 days. MAIN OUTCOMES: Primary Outcome Measures: Change from Baseline amount of SARS-CoV-2 in salivary samples at 4 and 9 hours, 1, 2, 3, 4, 5 and 6 days. Real-time PCR assays are performed to assess salivary SARS-CoV 2 viral load. SECONDARY OUTCOME MEASURES: Change from Baseline amount of SARS-CoV-2 virus in nasal samples at 6 days. Real-time PCR assays are performed to assess nasal SARS-CoV-2 viral load. RANDOMISATION: Participants meeting all eligibility requirements are allocated to one of the two study arms (mouthwash with ß-cyclodextrin and Citrox® or mouthwash without ß-cyclodextrin and Citrox®) in a 1:1 ratio using simple randomisation with computer generated random numbers. BLINDING (MASKING): Participants, doctors and nurses caring for participants, laboratory technicians and investigators assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Both the intervention and control groups will be composed of 103 participants, so the study will include a total of 206 participants. TRIAL STATUS: The current protocol version is 6, August 4th, 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. As of October 2, 2020, forty-two participants have been included. TRIAL REGISTRATION: This trial was registered on 20 April 2020 at www.clinicaltrials.gov with the number NCT04352959 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol." The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)."


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus , Antissépticos Bucais , Cavidade Nasal/virologia , Pandemias , Pneumonia Viral , Saliva/virologia , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Antissépticos Bucais/administração & dosagem , Antissépticos Bucais/efeitos adversos , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Carga Viral , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/efeitos adversos
13.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-33184246

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial π-π interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Oxazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Antivirais/química , Antivirais/uso terapêutico , Infecções por Coronavirus/virologia , Humanos , Laxantes/química , Laxantes/uso terapêutico , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Conformação Proteica
14.
Molecules ; 25(21)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33137894

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which caused novel corona virus disease-2019 (COVID-19) pandemic, necessitated a global demand for studies related to genes and enzymes of SARS-CoV2. SARS-CoV2 infection depends on the host cell Angiotensin-Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease-2 (TMPRSS2), where the virus uses ACE2 for entry and TMPRSS2 for S protein priming. The TMPRSS2 gene encodes a Transmembrane Protease Serine-2 protein (TMPS2) that belongs to the serine protease family. There is no crystal structure available for TMPS2, therefore, a homology model was required to establish a putative 3D structure for the enzyme. A homology model was constructed using SWISS-MODEL and evaluations were performed through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). Molecular dynamics simulations were employed to investigate the stability of the constructed model. Docking of TMPS2 inhibitors, camostat, nafamostat, gabexate, and sivelestat, using Molecular Operating Environment (MOE) software, into the constructed model was performed and the protein-ligand complexes were subjected to MD simulations and computational binding affinity calculations. These in silico studies determined the tertiary structure of TMPS2 amino acid sequence and predicted how ligands bind to the model, which is important for drug development for the prevention and treatment of COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Serina Endopeptidases/química , Inibidores de Serino Proteinase/farmacologia , Antivirais/química , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Gabexato/análogos & derivados , Gabexato/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Guanidinas/farmacologia , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/metabolismo , Sulfonamidas/farmacologia
15.
Molecules ; 25(21)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33142770

RESUMO

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Despite containment measures, SARS-CoV-2 spread in Asia, Southern Europe, then in America and currently in Africa. Identifying effective antiviral drugs is urgently needed. An efficient approach to drug discovery is to evaluate whether existing approved drugs can be efficient against SARS-CoV-2. Doxycycline, which is a second-generation tetracycline with broad-spectrum antimicrobial, antimalarial and anti-inflammatory activities, showed in vitro activity on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) with median effective concentration (EC50) of 4.5 ± 2.9 µM, compatible with oral uptake and intravenous administrations. Doxycycline interacted both on SARS-CoV-2 entry and in replication after virus entry. Besides its in vitro antiviral activity against SARS-CoV-2, doxycycline has anti-inflammatory effects by decreasing the expression of various pro-inflammatory cytokines and could prevent co-infections and superinfections due to broad-spectrum antimicrobial activity. Therefore, doxycycline could be a potential partner of COVID-19 therapies. However, these results must be taken with caution regarding the potential use in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results to actual clinical treatment in patients. In vivo evaluation in animal experimental models is required to confirm the antiviral effects of doxycycline on SARS-CoV-2 and more trials of high-risk patients with moderate to severe COVID-19 infections must be initiated.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Doxiciclina/farmacologia , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Chlorocebus aethiops , Cloroquina/farmacologia , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Células Vero
16.
Biomolecules ; 10(11)2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33147723

RESUMO

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.


Assuntos
Antivirais/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Plantas/química , Triterpenos/química , Triterpenos/metabolismo
17.
Biomedica ; 40(Supl. 2): 80-95, 2020 10 30.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33152192

RESUMO

Introduction: Recently, researchers from China and France reported on the effectiveness of chloroquine and hydroxychloroquine for the inhibition of SARS-CoV-2 viral replication in vitro. Timely dissemination of scientific information is key in times of pandemic. A systematic review of the effect and safety of these drugs on COVID-19 is urgently needed. Objective: To map published studies until March 25, 2020, on the use of chloroquine and its derivates in patients with COVID-19. Materials and methods: We searched on PubMed, Embase, Lilacs, and 15 registries from the World Health Organization's International Clinical Trials Registry Platform for theoretical and empirical research in English, Spanish, Italian, French, or Portuguese until March 25, 2020, and made a narrative synthesis of the results. Results: We included 19 records and 24 trial registries (n=43) including 18,059 patients. China registered 66% (16/24) of the trials. Nine trials evaluate chloroquine exclusively and eight hydroxychloroquine. The records are comments (n=9), in vitro studies (n=3), narrative reviews (n=2), clinical guidelines (n=2), as well as a systematic review, an expert consensus, and a clinical trial. Conclusions: One small (n=26), non-randomized, and flawed clinical trial supports hydroxychloroquine use in patients with COVID-19. There is an urgent need for more clinical trial results to determine the effect and safety of chloroquine and hydroxychloroquine on COVID-19.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/efeitos adversos , Antivirais/farmacologia , Betacoronavirus/fisiologia , Cloroquina/efeitos adversos , Cloroquina/farmacologia , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo , Síndrome da Liberação de Citocina/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia , Estudos Multicêntricos como Assunto , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
18.
J Mol Model ; 26(12): 340, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184722

RESUMO

Among targets selected for studies aimed at identifying potential inhibitors against COVID-19, SARS-CoV2 main proteinase (Mpro) is highlighted. Mpro is indispensable for virus replication and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 Mpro, drug repurposing, and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 Mpro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric Mpro most significantly impacts binding affinity tendency compared with the monomeric state, which suggests that dimeric state is most useful when performing studies aimed at identifying drugs targeting Mpro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 Mpro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin, and bortezomib), which were identified as the best candidates for the treatment of COVID-19 in some previous dockings studies involving monomeric SARS-CoV2 Mpro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 Mpro; therefore, the compound may have clinical utility against COVID-19. Graphical abstract.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Saquinavir/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteases/química , Multimerização Proteica , Saquinavir/química
19.
F1000Res ; 9: 674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123349

RESUMO

Background: The ability to protect workers and healthcare professionals from infection by SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is of great concern. Hospitals, nursing homes and employers are adopting infection control strategies based on guidance from leading public health organizations such as the CDC, OSHA, FDA, and other government bodies. Certain hard surface disinfectants are effective against SARS-CoV-2 but are not suitable for use on skin or personal protective equipment (PPE) that comes into contact with skin. Furthermore, near-ubiquitous alcohol-based hand sanitizers are acceptable for use on skin, but they are not suitable for use on PPE. PPE, especially masks, are also commonly being used for longer durations than normal. There is a need for new products and techniques that can effectively disinfect PPE during wear time without having detrimental effects on surrounding skin. Clyraguard spray is a novel copper iodine complex designed to be used on non-critical PPE. Methods: In this study, the Clyraguard copper iodine complex was tested for its ability to inactivate SARS-CoV-2 in solution. Results: These data indicate the product to be effective in reducing SARS-CoV-2 titers in a time-dependent manner, with the virus being reduced below the detection limits within 30 minutes. Conclusions: These results suggest that Clyraguard may be an effective tool for mitigating cross-contamination of non-critical PPE that may come into contact with SARS-CoV-2.


Assuntos
Betacoronavirus/efeitos dos fármacos , Cobre/farmacologia , Desinfetantes/farmacologia , Iodo/farmacologia , Inativação de Vírus/efeitos dos fármacos , Infecções por Coronavirus , Humanos , Pandemias , Pneumonia Viral
20.
F1000Res ; 9: 1203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33145015

RESUMO

Background: In 2020, the world has struggled to deal with coronavirus disease 2019 (COVID-19), which started in 2019 in China and has spread throughout the globe, affecting at least 31,175,835 humans globally and claiming 962,634 lives reported till 22nd September, 2020 by the World Health Organization. The main causative agent for this disease is known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). So far, there is no cure or proven therapeutics available till date. Therefore, we undertook this study to find the most probable drug candidate through a bioinformatics study. Methods: Thus, we virtually screened the Zinc natural database using HTVS tool through molecular docking studies to analyze molecules recommended for the treatment of COVID-19. Results: Ramipril benzyl ester, propafenone dimer and Lariciresinol are three important drugs found from the present study due to their medicinal application which could be helpful in treating the disease. Stylopine, quillaic acid, cinobufagin, vitisinol C, segetalin A, scopolamine, 3-oxo glycyrrhetinic acid, conchinone B, lactimidomycin and cardinalins 4 are the other lead molecules that could be used as therapeutics against COVID-19 disease. Conclusions: The studied molecules could act as an effective inhibitory drug against COVID-19.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Biologia Computacional , Descoberta de Drogas , China , Infecções por Coronavirus/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico
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