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1.
BMC Bioinformatics ; 22(Suppl 3): 293, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-34074242

RESUMEN

BACKGROUND: Drug repositioning, meanings finding new uses for existing drugs, which can accelerate the processing of new drugs research and development. Various computational methods have been presented to predict novel drug-disease associations for drug repositioning based on similarity measures among drugs and diseases. However, there are some known associations between drugs and diseases that previous studies not utilized. METHODS: In this work, we develop a deep gated recurrent units model to predict potential drug-disease interactions using comprehensive similarity measures and Gaussian interaction profile kernel. More specifically, the similarity measure is used to exploit discriminative feature for drugs based on their chemical fingerprints. Meanwhile, the Gaussian interactions profile kernel is employed to obtain efficient feature of diseases based on known disease-disease associations. Then, a deep gated recurrent units model is developed to predict potential drug-disease interactions. RESULTS: The performance of the proposed model is evaluated on two benchmark datasets under tenfold cross-validation. And to further verify the predictive ability, case studies for predicting new potential indications of drugs were carried out. CONCLUSION: The experimental results proved the proposed model is a useful tool for predicting new indications for drugs or new treatments for diseases, and can accelerate drug repositioning and related drug research and discovery.


Asunto(s)
Aprendizaje Profundo , Reposicionamiento de Medicamentos , Algoritmos , Biología Computacional , Simulación por Computador
2.
Nat Commun ; 12(1): 3309, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-34083527

RESUMEN

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.


Asunto(s)
Antivirales/farmacología , COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , Pandemias , SARS-CoV-2 , Animales , COVID-19/prevención & control , COVID-19/virología , Línea Celular , Citidina/administración & dosificación , Citidina/análogos & derivados , Citidina/farmacología , Bases de Datos Farmacéuticas , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Células HeLa , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/farmacología , Mesocricetus , Nelfinavir/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Replicación Viral/efectos de los fármacos
3.
Int J Mol Sci ; 22(11)2021 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-34067243

RESUMEN

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.


Asunto(s)
Antiinflamatorios/farmacología , Antivirales/farmacología , COVID-19/dietoterapia , Cafeína/farmacología , Reposicionamiento de Medicamentos/métodos , Músculo Liso/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , COVID-19/metabolismo , COVID-19/fisiopatología , Humanos , Factores Inmunológicos/farmacología , Simulación de Dinámica Molecular , Músculo Liso/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo
4.
Int J Mol Sci ; 22(9)2021 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-34063231

RESUMEN

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types.


Asunto(s)
Antineoplásicos/farmacología , Antivirales/farmacología , COVID-19/metabolismo , Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , SARS-CoV-2/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , COVID-19/complicaciones , Reposicionamiento de Medicamentos , Receptores ErbB/metabolismo , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/virología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Transducción de Señal/genética
5.
Int J Mol Sci ; 22(11)2021 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-34063964

RESUMEN

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , SARS-CoV-2/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antivirales/química , Antivirales/farmacología , COVID-19/fisiopatología , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Replicación Viral/efectos de los fármacos
6.
Int J Mol Sci ; 22(11)2021 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-34064287

RESUMEN

Therapeutics and vaccines against the COVID-19 pandemic need to be developed rapidly and efficiently, given its severity. To maximize the efficiency and productivity of drug development, the world has adopted disruptive technologies and approaches in various drug development areas. Telehealth, characterized by the heavy use of digital technologies; drug repositioning strategies, aided by computational breakthroughs; and data tracking tool hubs, enabling real-time information sharing, have received much attention. Moreover, drug developers have engaged in open innovation by establishing various types of collaborations, many of which have been carried out across nations and enterprises. Finally, regulatory agencies have attempted to operate on a more flexible review basis than before. Although such disruptive approaches have partly reshaped drug development practices, issues and challenges remain before the completion of this paradigm shift in conventional drug development practices for the post-pandemic era. In this review, we have highlighted the role of a collaborative community of experts in order to figure out how disruptive technologies can be fully integrated into the current drug development practices and improve drug development efficiency for the post-pandemic era.


Asunto(s)
COVID-19/tratamiento farmacológico , Desarrollo de Medicamentos/métodos , Reposicionamiento de Medicamentos/métodos , Informática Médica/métodos , Telemedicina/métodos , Humanos , Pandemias , SARS-CoV-2
7.
Biomolecules ; 11(6)2021 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-34071060

RESUMEN

COVID-19 is a devastating respiratory and inflammatory illness caused by a new coronavirus that is rapidly spreading throughout the human population. Over the past 12 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has already infected over 160 million (>20% located in United States) and killed more than 3.3 million people around the world (>20% deaths in USA). As we face one of the most challenging times in our recent history, there is an urgent need to identify drug candidates that can attack SARS-CoV-2 on multiple fronts. We have therefore initiated a computational dynamics drug pipeline using molecular modeling, structure simulation, docking and machine learning models to predict the inhibitory activity of several million compounds against two essential SARS-CoV-2 viral proteins and their host protein interactors-S/Ace2, Tmprss2, Cathepsins L and K, and Mpro-to prevent binding, membrane fusion and replication of the virus, respectively. All together, we generated an ensemble of structural conformations that increase high-quality docking outcomes to screen over >6 million compounds including all FDA-approved drugs, drugs under clinical trial (>3000) and an additional >30 million selected chemotypes from fragment libraries. Our results yielded an initial set of 350 high-value compounds from both new and FDA-approved compounds that can now be tested experimentally in appropriate biological model systems. We anticipate that our results will initiate screening campaigns and accelerate the discovery of COVID-19 treatments.


Asunto(s)
Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/química , Antivirales/metabolismo , Antivirales/farmacología , Sitios de Unión , COVID-19/patología , COVID-19/virología , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Humanos , Aprendizaje Automático , Simulación del Acoplamiento Molecular , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Serina Endopeptidasas/química , Serina Endopeptidasas/metabolismo , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas del Envoltorio Viral/metabolismo , Replicación Viral/efectos de los fármacos
8.
J Enzyme Inhib Med Chem ; 36(1): 1230-1235, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34074197

RESUMEN

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.


Asunto(s)
Acetazolamida/uso terapéutico , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasas Carbónicas/sangre , Equilibrio Ácido-Base/efectos de los fármacos , Mal de Altura/sangre , Mal de Altura/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Bicarbonatos/sangre , COVID-19/sangre , COVID-19/diagnóstico por imagen , COVID-19/virología , Dióxido de Carbono/sangre , Tos/sangre , Tos/tratamiento farmacológico , Tos/patología , Tos/virología , Reposicionamiento de Medicamentos , Disnea/sangre , Disnea/tratamiento farmacológico , Disnea/patología , Disnea/virología , Fiebre/sangre , Fiebre/tratamiento farmacológico , Fiebre/patología , Fiebre/virología , Humanos , Concentración de Iones de Hidrógeno , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/sangre , Hipoxia/tratamiento farmacológico , Hipoxia/patología , Hipoxia/virología , Oximetría , Proyectos de Investigación , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X
9.
Mayo Clin Proc ; 96(6): 1592-1608, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34088418

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic continues its global spread. Coordinated effort on a vast scale is required to halt its progression and to save lives. Electronic health record (EHR) data are a valuable resource to mitigate the COVID-19 pandemic. We review how the EHR could be used for disease surveillance and contact tracing. When linked to "omics" data, the EHR could facilitate identification of genetic susceptibility variants, leading to insights into risk factors, disease complications, and drug repurposing. Real-time monitoring of patients could enable early detection of potential complications, informing appropriate interventions and therapy. We reviewed relevant articles from PubMed, MEDLINE, and Google Scholar searches as well as preprint servers, given the rapidly evolving understanding of the COVID-19 pandemic.


Asunto(s)
COVID-19/epidemiología , Registros Electrónicos de Salud , COVID-19/diagnóstico , COVID-19/prevención & control , Trazado de Contacto/métodos , Reposicionamiento de Medicamentos , Monitoreo Epidemiológico , Humanos , SARS-CoV-2/genética
10.
Sci Rep ; 11(1): 10220, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33986382

RESUMEN

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , Reposicionamiento de Medicamentos/métodos , Epítopos/inmunología , Humanos , Ipilimumab/inmunología , Ipilimumab/farmacología , Simulación del Acoplamiento Molecular , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología
11.
Sci Rep ; 11(1): 10290, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33986405

RESUMEN

As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.


Asunto(s)
Amidas/farmacología , Carbamatos/farmacología , Ciclopropanos/farmacología , Reposicionamiento de Medicamentos , Inhibidores Enzimáticos/farmacología , Quinoxalinas/farmacología , ARN Helicasas/antagonistas & inhibidores , SARS-CoV-2/enzimología , Sulfonamidas/farmacología , Triazoles/farmacología , Antivirales/farmacología , COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Dominios Proteicos/efectos de los fármacos , ARN Helicasas/química , ARN Helicasas/metabolismo , SARS-CoV-2/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteínas Virales/metabolismo
12.
Curr Cardiol Rep ; 23(6): 62, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33961142

RESUMEN

PURPOSE OF REVIEW: Drug development has evolved over the years from being one-at-a-time to be massive screens in an industrial manner. Bringing a new therapeutic agent from concept to bedside can take a decade and cost billions of dollars-with most concepts failing along the way. Of the few compounds that make it to clinical testing, less than one out of eight make it to approval. This traditional drug development pipeline is challenging for prevalent diseases and makes the development of new therapeutics for rare diseases financially intractable. RECENT FINDINGS: Repurposing of drugs is an alternative to identify new applications for the thousands of compounds that have already been approved for clinical use. There is now a range of strategies for such efforts that leverage clinical data, pharmacologic data, and/or genomic or transcriptomic data. These strategies, together with examples, are detailed in this review. Drug repurposing bypasses the pre-clinical work and thereby opens up the opportunity to provide targeted treatment at a fraction of the cost that is accompanied with the development from ideation to full approval. Such an approach makes drug discovery for any disease process more efficient but holds particular promise for rare diseases for which there is little to no other viable drug development channel.


Asunto(s)
Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Genómica , Humanos
13.
J Environ Public Health ; 2021: 6631721, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33953756

RESUMEN

Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.


Asunto(s)
Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , SARS-CoV-2 , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Humanos , Terapia Molecular Dirigida
14.
Cell Rep ; 35(7): 109133, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-33984267

RESUMEN

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir.


Asunto(s)
Antivirales/farmacología , COVID-19/tratamiento farmacológico , Proteasas Similares a la Papaína de Coronavirus/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , COVID-19/virología , Técnicas de Cultivo de Célula , Línea Celular , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Reposicionamiento de Medicamentos/métodos , Sinergismo Farmacológico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacología , Replicación Viral/efectos de los fármacos
15.
Neurology ; 96(18): e2313-e2322, 2021 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-34038379

RESUMEN

OBJECTIVE: To assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon 2-stage design. METHODS: We enrolled patients in an open-label, Simon 2-stage, single-center, phase 2, single-arm futility trial at the Calgary Multiple Sclerosis Clinic if they met the following criteria: age of 18 to 60 years, SPMS, screening Expanded Disability Status Scale score of 4.0 to 6.5, and screening timed 25-ft walk (T25FW) of ≥9 seconds. Patients received domperidone 10 mg 4 times daily for 1 year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by ≥20% at 12 months compared to baseline. This trial is registered with ClinicalTrials.gov (NCT02308137). RESULTS: Between February 13, 2015, and January 3, 2020, 110 patients were screened, 81 received treatment, and 64 completed follow-up, of whom 62 were analyzed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40% and above the predefined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients. CONCLUSIONS: Domperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon 2-stage trial model may be a useful model for phase 2 studies in progressive MS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02308137. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in individuals with SPMS participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.


Asunto(s)
Domperidona/uso terapéutico , Antagonistas de Dopamina/uso terapéutico , Reposicionamiento de Medicamentos/métodos , Inutilidad Médica , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/epidemiología
17.
Immunopharmacol Immunotoxicol ; 43(3): 265-270, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34057870

RESUMEN

Understanding the exact role of current drugs in Covid-19 disease is essential in the era of global pandemics. Metformin which prescribed as the first-line treatment of type 2 diabetes has beneficial effects on Sars-cov2 infection. These effects are including regulation of immune system, Renin-Angiotensin System and Dipeptidyl Peptidase 4 function in Covid-19 infection. It also activates ACE2, the main receptor of Sars-cov2, in the epithelial cells of respiratory tissue through AMPK signaling and subsequently decreases the rate of viral adhesion. Metformin also declines the adherence of Sars-cov2 to DPP4 (the other receptor of the virus) on T cells. Hence, regulatory effects of metformin on membranous ACE2, and DPP4 can modulate immune reaction against Sars-cov2. Also, immunometabolic effects of metformin on inflammatory cells impair hyper-reactive immune response against the virus through reduction of glycolysis and propagation of mitochondrial oxidation. Metformin also decreases platelet aggravation and risk of thrombosis. In this article, we argue that metformin has beneficial effects on Covid-19 infection in patients with type 2 diabetes and insulin resistance. This opinion should be investigated in future clinical trials.


Asunto(s)
COVID-19/tratamiento farmacológico , Diabetes Mellitus Tipo 2 , Reposicionamiento de Medicamentos , Resistencia a la Insulina , Metformina/uso terapéutico , SARS-CoV-2 , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos
18.
J Clin Neurosci ; 88: 163-172, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33992179

RESUMEN

The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people's mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.


Asunto(s)
COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos , Inhibidores de la Captación de Serotonina/uso terapéutico , Antiinflamatorios/uso terapéutico , COVID-19/complicaciones , Fluoxetina/uso terapéutico , Humanos , Pandemias
19.
Sci Rep ; 11(1): 9378, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33931664

RESUMEN

The Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus needs a fast recognition of effective drugs to save lives. In the COVID-19 situation, finding targets for drug repurposing can be an effective way to present new fast treatments. We have designed a two-step solution to address this approach. In the first step, we identify essential proteins from virus targets or their associated modules in human cells as possible drug target candidates. For this purpose, we apply two different algorithms to detect some candidate sets of proteins with a minimum size that drive a significant disruption in the COVID-19 related biological networks. We evaluate the resulted candidate proteins sets with three groups of drugs namely Covid-Drug, Clinical-Drug, and All-Drug. The obtained candidate proteins sets approve 16 drugs out of 18 in the Covid-Drug, 273 drugs out of 328 in the Clinical-Drug, and a large number of drugs in the All-Drug. In the second step, we study COVID-19 associated proteins sets and recognize proteins that are essential to disease pathology. This analysis is performed using DAVID to show and compare essential proteins that are contributed between the COVID-19 comorbidities. Our results for shared proteins show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases.


Asunto(s)
COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos , Mapas de Interacción de Proteínas , Antivirales/uso terapéutico , COVID-19/metabolismo , Sistemas de Liberación de Medicamentos , Interacciones Huésped-Patógeno , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Transducción de Señal/efectos de los fármacos
20.
Indian J Pharmacol ; 53(1): 63-72, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33976001

RESUMEN

COVID-19 pandemic led to an unprecedented collaborative effort among industry, academia, regulatory bodies, and governments with huge financial investments. Scientists and researchers from India also left no stone unturned to find therapeutic and preventive measures against COVID-19. Indian pharmaceutical companies are one of the leading manufacturers of vaccine in the world, are utilizing its capacity to its maximum, and are one among the forerunners in vaccine research against COVID-19 across the globe. In this systematic review, the information regarding contribution of Indian scientists toward COVID-19 research has been gathered from various news articles across Google platform apart from searching PubMed, WHO site, COVID-19 vaccine tracker, CTRI, clinicaltrials.gov, and websites of pharmaceutical companies. The article summarizes and highlights the various therapeutic and vaccine candidates, diagnostic kits, treatment agents, and technology being developed and tested by Indian researcher community against COVID-19.


Asunto(s)
Antivirales/uso terapéutico , Investigación Biomédica , Vacunas contra la COVID-19/uso terapéutico , COVID-19/tratamiento farmacológico , Desarrollo de Medicamentos , Descubrimiento de Drogas , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/efectos adversos , Inteligencia Artificial , COVID-19/diagnóstico , COVID-19/virología , Prueba de COVID-19 , Ensayos Clínicos como Asunto , Diseño Asistido por Computadora , Difusión de Innovaciones , Reposicionamiento de Medicamentos , Humanos , India , Valor Predictivo de las Pruebas , SARS-CoV-2/patogenicidad , Resultado del Tratamiento
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