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1.
J Chem Theory Comput ; 16(11): 7160-7172, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33090785

RESUMO

In the context of drug-receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CLpro) of SARS-CoV-2. The core structures of 3CLpro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The nature of binding in the 3CLpro active site and the involved residues besides the CYS-HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CLpro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.


Assuntos
Betacoronavirus/enzimologia , Cisteína Endopeptidases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Interface Usuário-Computador , Proteínas não Estruturais Virais/antagonistas & inibidores
2.
Comput Biol Med ; 126: 104046, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33065388

RESUMO

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.


Assuntos
Betacoronavirus/enzimologia , Ácidos Cafeicos/química , Infecções por Coronavirus/tratamento farmacológico , Curcumina/química , Cisteína Endopeptidases , Descoberta de Drogas , Lactatos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Proteínas não Estruturais Virais , Ácidos Cafeicos/uso terapêutico , Infecções por Coronavirus/enzimologia , Curcumina/uso terapêutico , Cisteína Endopeptidases/química , Humanos , Lactatos/uso terapêutico , Pandemias , Pneumonia Viral/enzimologia , Inibidores de Proteases/uso terapêutico , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
3.
Med. clín (Ed. impr.) ; 155(7): 281-287, oct. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-191724

RESUMO

OBJETIVOS: Determinar la prevalencia de interacciones potenciales en pacientes COVID-19 en tratamiento con lopinavir/ritonavir (LPV/r). El objetivo secundario fue elaborar recomendaciones e identificar los factores de riesgo asociados a presentar interacciones potenciales con LPV/r. SUJETOS Y MÉTODOS: Estudio transversal y multicéntrico con la participación de 2 hospitales. Se incluyeron pacientes COVID-19 mayores de 18 años, con ingreso hospitalario y en tratamiento con LPV/r. Se realizó un cribado de las interacciones potenciales relacionadas con LPV/r y la medicación domiciliaria y hospitalaria. Se utilizó como base de datos de consulta Lexicomp® (Uptodate), HIV-drug interacctions y COVID-drug interacctions. RESULTADOS: Se incluyeron 361 pacientes con una media de edad de 62,77 ± 14,64 años, donde el 59,6% (n = 215) fueron hombres. El 62,3% (n=225) tuvieron una o más interacciones potenciales y el 26, 87% (n = 97) 2 o más. Las variables independientes asociadas a presentar ≥ 1 interacciones potenciales fueron la edad (> 65) (OR 1,95; IC 95% 1,06-3,59; P = 0,033), el ingreso en UCI (OR 9,22; IC 95% 1,98-42,93; P = 0,005), la enfermedad previa respiratoria (OR 2,90; IC 95% 1,15-7,36; P = 0,024), psiquiátrica (OR 4,14; IC 95% 1,36-12,61; P = 0,013), la dislipemia (OR 3,21; IC 95% 1,63-6,35; P = 0,001) y el número de fármacos prescrito (OR 4,33; IC 95% 2,40-7,81; P = 0,000). CONCLUSIÓN: La prevalencia de interacciones potenciales en paciente COVID-19 en tratamiento con LPV/r es elevada, comportándose como factores de riesgo asociados la edad (> 65), el ingreso en UCI, la enfermedad previa respiratoria, psiquiátrica y la dislipemia y el número de fármacos prescritos


OBJECTIVES: To determine the prevalence of potential interactions in COVID-19 patients receiving lopinavir/ritonavir (LPV/r). The secondary objective was to develop recommendations and identify the risk factors associated with presenting potential interactions with LPV/r. SUBJECTS AND METHODS: Cross-sectional and multicenter study with the participation of 2 hospitals. COVID-19 patients over 18 years of age, admitted to hospital and under treatment with LPV/r were included. A screening of potential interactions related to LPV/r and home and hospital medication was carried out. Lexicomp® (Uptodate), HIV-drug interactions and COVID-drug interactions were used as the query database. RESULTS: 361 patients with a mean age of 62.77 ± 14.64 years were included, where 59.6% (n = 215) were men. 62.3% (n = 225) had 1 or more potential interactions and 26, 87% (n = 97) 2 or more. The independent variables associated with presenting ≥ 1 potential interactions were age (> 65) (OR 1.95; 95% CI 1.06-3.59, P =.033), ICU admission (OR 9.22; CI 95% 1.98-42.93; P = .005), previous respiratory pathology (OR 2.90; 95% CI 1.15-7.36; P =.024), psychiatric (OR 4.14; 95 CI % 1.36-12.61; P =.013), dyslipidemia (OR 3.21; 95% CI 1.63-6.35; P = .001) and the number of drugs prescribed (OR 4.33; 95% CI 2.40-7.81; P =.000). CONCLUSION: The prevalence of potential interactions in COVD-19 patient undergoing treatment with LPV/r is high, with age (> 65), ICU admission, previous respiratory and psychiatric pathology, dyslipidemia and the number of prescribed drugs acting as risk factors


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Infecções por Coronavirus/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Fatores de Risco , Pneumonia Viral/tratamento farmacológico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Interações Medicamentosas , Inibidores de Proteases/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Segurança do Paciente
4.
Molecules ; 25(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867349

RESUMO

Three types of new coronaviruses (CoVs) have been identified recently as the causative viruses for the severe pneumonia-like respiratory illnesses, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and corona-virus disease 2019 (COVID-19). Neither therapeutic agents nor vaccines have been developed to date, which is a major drawback in controlling the present global pandemic of COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) and has resulted in more than 20,439,814 cases and 744,385 deaths. Each of the 3C-like (3CL) proteases of the three CoVs is essential for the proliferation of the CoVs, and an inhibitor of the 3CL protease (3CLpro) is thought to be an ideal therapeutic agent against SARS, MERS, or COVID-19. Among these, SARS-CoV is the first corona-virus isolated and has been studied in detail since the first pandemic in 2003. This article briefly reviews a series of studies on SARS-CoV, focusing on the development of inhibitors for the SARS-CoV 3CLpro based on molecular interactions with the 3CL protease. Our recent approach, based on the structure-based rational design of a novel scaffold for SARS-CoV 3CLpro inhibitor, is also included. The achievements summarized in this short review would be useful for the design of a variety of novel inhibitors for corona-viruses, including SARS-CoV-2.


Assuntos
Antivirais/química , Betacoronavirus/química , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Inibidores de Proteases/química , Vírus da SARS/patogenicidade , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/classificação , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Domínio Catalítico , Infecções por Coronavirus/tratamento farmacológico , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Humanos , Cinética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/classificação , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/genética , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Especificidade por Substrato , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
5.
Viruses ; 12(10)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993173

RESUMO

The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/fisiologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/virologia , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Humanos , Pandemias , Peptídeos/uso terapêutico , Pneumonia Viral/virologia , Inibidores de Proteases/uso terapêutico
6.
Int J Med Sci ; 17(14): 2133-2146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922174

RESUMO

The SARS-CoV-2 spread quickly across the globe. The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic. The mortality rate, hospital disorders and incalculable economic and social damages, besides the unproven efficacy of the treatments evaluated against COVID-19, raised the need for immediate control of this disease. Therefore, the current study employed in silico tools to rationally identify new possible SARS-CoV-2 main protease (Mpro) inhibitors. That is an enzyme conserved among the coronavirus species; hence, the identification of an Mpro inhibitor is to make it a broad-spectrum drug. Molecular docking studies described the binding sites and the interaction energies of 74 Mpro-ligand complexes deposited in the Protein Data Bank (PDB). A structural similarity screening was carried out in order to identify possible Mpro ligands that show additional pharmacological properties against COVID-19. We identified 59 hit compounds and among them, melatonin stood out due to its prominent immunomodulatory and anti-inflammatory activities; it can reduce oxidative stress, defence cell mobility and efficiently combat the cytokine storm and sepsis. In addition, melatonin is an inhibitor of calmodulin, an essential intracellular component to maintain angiotensin-converting enzyme 2 (ACE-2) on the cell surface. Interestingly, one of the most promising hits in our docking study was melatonin. It revealed better interaction energy with Mpro compared to ligands in complexes from PDB. Consequently, melatonin can have response potential in early stages for its possible effects on ACE-2 and Mpro, although it is also promising in more severe stages of the disease for its action against hyper-inflammation. These results definitely do not confirm antiviral activity, but can rather be used as a basis for further preclinical and clinical trials.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Melatonina/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Melatonina/uso terapêutico , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico
7.
Respiration ; 99(8): 667-677, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756065

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a potentially fatal disease that is of great global public health concern. OBJECTIVE: We explored the clinical management of inpatients with COVID-19 in Italy. METHODS: A self-administered survey was sent by email to Italian physicians caring for adult patients with COVID-19. A panel of experts was selected according to their clinical curricula and their responses were analyzed. RESULTS: A total of 1,215 physicians completed the survey questionnaire (17.4% response rate). Of these, 188 (15.5%) were COVID-19 experts. Chest computed tomography was the most used method to detect and monitor COVID-19 pneumonia. Most of the experts managed acute respiratory failure with CPAP (56.4%), high flow nasal cannula (18.6%), and non-invasive mechanical ventilation (8%), while an intensivist referral for early intubation was requested in 17% of the cases. Hydroxychloroquine was prescribed as an antiviral in 90% of cases, both as monotherapy (11.7%), and combined with protease inhibitors (43.6%) or azithromycin (36.2%). The experts unanimously prescribed low-molecular-weight heparin to patients with severe COVID-19 pneumonia, and half of them (51.6%) used a dose higher than standard. The respiratory burden in patients who survived the acute phase was estimated as relevant in 28.2% of the cases, modest in 39.4%, and negligible in 9%. CONCLUSIONS: In our survey some major topics, such as the role of non-invasive respiratory support and drug treatments, show disagreement between experts, likely reflecting the absence of high-quality evidence studies. Considering the significant respiratory sequelae reported following COVID-19, proper respiratory and physical therapy programs should be promptly made available.


Assuntos
Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Hospitalização , Pneumonia Viral/terapia , Padrões de Prática Médica , Inibidores de Proteases/uso terapêutico , Respiração Artificial/métodos , Insuficiência Respiratória/terapia , Adulto , Idoso , Anticoagulantes/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus , Cânula , Cardiologia , Pressão Positiva Contínua nas Vias Aéreas/métodos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Cuidados Críticos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Medicina Interna , Itália , Pulmão/diagnóstico por imagem , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Pandemias , Médicos , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumologia , Encaminhamento e Consulta , Insuficiência Respiratória/etiologia , Inquéritos e Questionários , Tomografia Computadorizada por Raios X
8.
Bioessays ; 42(11): e2000094, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32815593

RESUMO

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Infecções por Coronavirus/epidemiologia , Reposicionamento de Medicamentos/métodos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pandemias , Papaína/antagonistas & inibidores , Papaína/metabolismo , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Embolia Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Insuficiência Respiratória/prevenção & controle , Choque Séptico/prevenção & controle , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos
9.
Eur J Med Chem ; 206: 112702, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798789

RESUMO

SARS-CoV-2 3C-like protease is the main protease of SARS-CoV-2 and has been considered as one of the key targets for drug discovery against COVID-19. We identified several N-substituted isatin compounds as potent SARS-CoV-2 3C-like protease inhibitors. The three most potent compounds inhibit SARS-CoV-2 3C-like protease with IC50's of 45 nM, 47 nM and 53 nM, respectively. Our study indicates that N-substituted isatin compounds have the potential to be developed as broad-spectrum anti-coronavirus drugs.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Isatina/uso terapêutico , Inibidores de Proteases/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Cisteína Endopeptidases , Humanos , Isatina/análogos & derivados , Isatina/síntese química , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 206: 112711, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810751

RESUMO

This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.


Assuntos
Antivirais/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/uso terapêutico , Cisteína Endopeptidases , Humanos , Peptidomiméticos , Inibidores de Proteases/uso terapêutico
11.
Commun Biol ; 3(1): 374, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641750

RESUMO

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Neoplasias da Próstata/epidemiologia , Distribuição por Sexo , Antineoplásicos Hormonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Betacoronavirus/ultraestrutura , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Reposicionamento de Medicamentos , Feminino , Previsões , Hormônios Esteroides Gonadais/fisiologia , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Inibidores de Proteases/uso terapêutico , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Fatores de Risco , Serina Endopeptidases/biossíntese , Serina Endopeptidases/fisiologia , Estados Unidos/epidemiologia , Internalização do Vírus
12.
Medicine (Baltimore) ; 99(27): e20915, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629687

RESUMO

RATIONALE: Transmitted resistance to integrase strand inhibitors (INSTI) has been uncommon, but is slowly becoming more prevalent among those living with HIV. In an era with 2-drug regimens for antiretroviral therapy, transmitted resistance for INSTI is alarming. PATIENT CONCERNS: A 28-year-old African American female was recently diagnosed with HIV during a 30-week prenatal visit. DIAGNOSIS: HIV 4th generation test was positive as well as confirmation. Genotype was performed using next generation sequencing. INTERVENTIONS: Patient was initially rapidly started on a dolutegravir based regimen and changed to a protease inhibitor regimen once her genotype reported an S230R mutation. OUTCOMES: Patient became virally suppressed on antiretroviral therapy and delivered an HIV negative baby. LESSONS: INSTI resistance testing should be done for treatment-naïve and INSTI-naïve persons, particularly when considering 2 drug INSTI based regimens.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/genética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Diagnóstico Pré-Natal , Inibidores de Proteases/uso terapêutico , Adulto , Feminino , Genótipo , Infecções por HIV/virologia , Humanos , Mutação , Gravidez , Complicações Infecciosas na Gravidez/virologia , Inibidores de Proteases/administração & dosagem
14.
Biomolecules ; 10(6)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599963

RESUMO

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Famotidina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Administração Intravenosa , Antivirais/administração & dosagem , Antivirais/farmacocinética , Simulação por Computador , Reposicionamento de Medicamentos , Famotidina/administração & dosagem , Famotidina/farmacocinética , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Replicação Viral/efeitos dos fármacos
15.
PLoS One ; 15(7): e0236447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697788

RESUMO

The hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) protease is a key component of the viral replication complex and the target of protease inhibitors used in current clinical practice. By cleaving and thereby inactivating selected host factors it also plays a role in the persistence and pathogenesis of hepatitis C. Here, we describe ovarian cancer immunoreactive antigen domain containing protein 1 (OCIAD1) as a novel cellular substrate of the HCV NS3-4A protease. OCIAD1 was identified by quantitative proteomics involving stable isotopic labeling using amino acids in cell culture coupled with mass spectrometry. It is a poorly characterized membrane protein believed to be involved in cancer development. OCIAD1 is cleaved by the NS3-4A protease at Cys 38, close to a predicted transmembrane segment. Cleavage was observed in heterologous expression systems, the replicon and cell culture-derived HCV systems, as well as in liver biopsies from patients with chronic hepatitis C. NS3-4A proteases from diverse hepacivirus species efficiently cleaved OCIAD1. The subcellular localization of OCIAD1 on mitochondria was not altered by NS3-4A-mediated cleavage. Interestingly, OCIAD2, a homolog of OCIAD1 with a cysteine residue in a similar position and identical subcellular localization, was not cleaved by NS3-4A. Domain swapping experiments revealed that the sequence surrounding the cleavage site as well as the predicted transmembrane segment contribute to substrate selectivity. Overexpression as well as knock down and rescue experiments did not affect the HCV life cycle in vitro, raising the possibility that OCIAD1 may be involved in the pathogenesis of hepatitis C in vivo.


Assuntos
Hepacivirus/enzimologia , Hepatite C Crônica/patologia , Interações entre Hospedeiro e Microrganismos , Proteínas de Neoplasias/metabolismo , Proteínas não Estruturais Virais/metabolismo , Biópsia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Células HEK293 , Hepacivirus/patogenicidade , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Fígado/patologia , Fígado/virologia , Mitocôndrias/metabolismo , Modelos Moleculares , Proteínas de Neoplasias/genética , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Domínios Proteicos/genética , Homologia de Sequência de Aminoácidos , Especificidade por Substrato/genética , Proteínas não Estruturais Virais/antagonistas & inibidores
16.
BMC Infect Dis ; 20(1): 524, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32689975

RESUMO

BACKGROUND: Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC). METHODS/DESIGN: A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures. DISCUSSION: We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations. TRIAL REGISTRATION: ISRCTN 44453201 , registered 19 June 2019 and EudraCT 2018-004732-30.


Assuntos
Adenina/análogos & derivados , Farmacorresistência Viral/genética , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adenina/uso terapêutico , Adulto , Combinação de Medicamentos , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Mutação , Projetos Piloto , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento
17.
Mol Neurobiol ; 57(10): 4106-4116, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32671688

RESUMO

The coronavirus disease of 2019 (COVID-19) is a pandemic disease that has taken the lives of many around the world. It is caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). To date, the USA, Italy, Spain, France, Russia, and the UK have been hit the hardest by the virus. However, death counts are still rising. Some nations have managed to "flatten" the death rate via protective measures such physical distancing, quarantine measures, and therapeutic management. The structure of the SARS-CoV-2 virus comprises of S proteins, M proteins, E proteins, hemagglutinin esterases, nucleocapsid proteins, and a 30-kb RNA genome. Viral proteases cleave these polyproteins and RNA-dependent polymerases replicate the genome. Currently, there are no effective therapies against this new disease. Numerous investigators are developing novel protease inhibitors, some of which have made it into clinical trials. Researchers are also attempting to develop a vaccine. In this review paper, we discuss the latest therapeutic developments against COVID-19. Graphical Abstract.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Inibidores de Proteases/uso terapêutico , Vacinas Virais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-32687406

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV), an enveloped virus with a positive-sense single-stranded RNA genome, facilitates the host cell entry through intricate interactions with proteins and lipids of the cell membrane. The detailed molecular mechanism involves binding to the host cell receptor and fusion at the plasma membrane or after being trafficked to late endosomes under favorable environmental conditions. A crucial event in the process is the proteolytic cleavage of the viral spike protein by the host's endogenous proteases that releases the fusion peptide enabling fusion with the host cellular membrane system. The present review details the mechanism of viral fusion with the host and highlights the therapeutic options that prevent SARS-CoV-2 entry in humans.


Assuntos
Betacoronavirus/metabolismo , Membrana Celular/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/metabolismo , Pneumonia Viral/prevenção & controle , Proteínas Virais de Fusão/metabolismo , Sequência de Aminoácidos , Animais , Betacoronavirus/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/virologia , Humanos , Peptidil Dipeptidase A/metabolismo , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas Virais de Fusão/efeitos dos fármacos
20.
Int J Mol Sci ; 21(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: covidwho-401521

RESUMO

In the past 17 years, three novel coronaviruses have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the coronavirus disease 2019 (COVID-19). As emerging infectious diseases, they were characterized by their novel pathogens and transmissibility without available clinical drugs or vaccines. This is especially true for the newly identified COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) for which, to date, no specific antiviral drugs or vaccines have been approved. Similar to SARS and MERS, the lag time in the development of therapeutics is likely to take months to years. These facts call for the development of broad-spectrum anti-coronavirus drugs targeting a conserved target site. This review will systematically describe potential broad-spectrum coronavirus fusion inhibitors, including antibodies, protease inhibitors, and peptide fusion inhibitors, along with a discussion of their advantages and disadvantages.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Inibidores de Proteínas Virais de Fusão/uso terapêutico , Animais , Betacoronavirus/fisiologia , Humanos , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacologia , Inibidores de Proteínas Virais de Fusão/efeitos adversos , Inibidores de Proteínas Virais de Fusão/farmacologia , Internalização do Vírus/efeitos dos fármacos
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