scholarly journals Network medicine framework for identifying drug-repurposing opportunities for COVID-19

2021 ◽  
Vol 118 (19) ◽  
pp. e2025581118
Author(s):  
Deisy Morselli Gysi ◽  
Ítalo do Valle ◽  
Marinka Zitnik ◽  
Asher Ameli ◽  
Xiao Gan ◽  
...  
Keyword(s):  
Viral Infection ◽  
De Novo ◽  
Drug Repurposing ◽  
Ground Truth ◽  
Neglected Diseases ◽  
Network Medicine ◽  
Novel Treatments ◽  
Predictive Algorithm ◽  
Predictive Methods ◽  
Network Proximity

The COVID-19 pandemic has highlighted the need to quickly and reliably prioritize clinically approved compounds for their potential effectiveness for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs experimentally screened in VeroE6 cells, as well as the list of drugs in clinical trials that capture the medical community’s assessment of drugs with potential COVID-19 efficacy. We find that no single predictive algorithm offers consistently reliable outcomes across all datasets and metrics. This outcome prompted us to develop a multimodal technology that fuses the predictions of all algorithms, finding that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We screened in human cells the top-ranked drugs, obtaining a 62% success rate, in contrast to the 0.8% hit rate of nonguided screenings. Of the six drugs that reduced viral infection, four could be directly repurposed to treat COVID-19, proposing novel treatments for COVID-19. We also found that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these network drugs rely on network-based mechanisms that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals Word embedding mining for SARS-CoV-2 and COVID-19 drug repurposing

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 585
Author(s):  
Finn Kuusisto ◽  
David Page ◽  
Ron Stewart
Keyword(s):  
De Novo ◽  
Drug Repurposing ◽  
Ground Truth ◽  
Biomedical Literature ◽  
Word Embedding ◽  
Electronic Health Record Data ◽  
Global Pandemic ◽  
Rapid Spread ◽  
Approved Drugs ◽  
Future Work

Background: The rapid spread of illness and death caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease 2019 (COVID-19) demands a rapid response in treatment development. Limitations of de novo drug development, however, suggest that drug repurposing is best suited to meet this demand. Methods: Due to the difficulty of accessing electronic health record data in general and in the midst of a global pandemic, and due to the similarity between SARS-CoV-2 and SARS-CoV, we propose mining the extensive biomedical literature for treatments to SARS that may also then be appropriate for COVID-19. In particular, we propose a method of mining a large biomedical word embedding for FDA approved drugs based on drug-disease treatment analogies. Results: We first validate that our method correctly identifies ground truth treatments for well-known diseases. We then use our method to find several approved drugs that have been suggested or are currently in clinical trials for COVID-19 in our top hits and present the rest as promising leads for further experimental investigation. Conclusions: We find our approach promising and present it, along with suggestions for future work, to the computational drug repurposing community at large as another tool to help fight the pandemic. Code and data for our methods can be found at https://github.com/finnkuusisto/covid19_word_embedding.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

scholarly journals Therapeutic clinical trials to combat COVID-19 pandemic in India: analysis from trial registry

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Angelika Batta ◽  
Raj Khirasaria ◽  
Vinod Kapoor ◽  
Deepansh Varshney
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Treatment Options ◽  
Drug Repurposing ◽  
Trial Registry ◽  
Therapeutic Treatment ◽  
Clinical Trial Registry ◽  
Clear Cut ◽  
Therapeutic Trials ◽  
Microsoft Office

AbstractObjectivesWith the emergence of Novel corona virus, hunt for finding a preventive and therapeutic treatment options has already begun at a rapid pace with faster clinical development programs. The present study was carried out to give an insight of therapeutic interventional trials registered under clinical trial registry of India (CTRI) for COVID-19 pandemic.MethodsAll trials registered under CTRI were evaluated using keyword “COVID” from its inception till 9th June 2020. Out of which, therapeutic interventional studies were chosen for further analysis. Following information was collected for each trial: type of therapeutic intervention (preventive/therapeutic), treatment given, no. of centers (single center/multicentric), type of institution (government/private), study design (randomized/single-blinded/double-blinded) and sponsors (Government/private). Microsoft Office Excel 2007 was used for tabulation and analysis.ResultsThe search yielded total of 205 trials, out of which, 127 (62%) trials were interventional trials. Out of these, 71 (56%) were AYUSH interventions, 36 (28.3%) tested drugs, 9 (7%) tested a nondrug intervention, rest were nutraceuticals and vaccines. About 66 (56%) were therapeutic trials. Majority were single-centered trials, i.e. 87 (73.7%). Trials were government funded in 57 (48.3%) studies. Majority were randomized controlled trials, i.e. 67 (56.8%). AYUSH preparations included AYUSH-64, Arsenic Album, SamshamaniVati etc.ConclusionsThe number of therapeutic interventional clinical trials was fair in India. A clear-cut need exists for an increase in both quantity and quality of clinical trials for COVID-19. Drug repurposing approach in all systems of medicine can facilitate prompt clinical decisions at lower costs than de novo drug development.

In Silico Modeling of FDA-Approved Drugs for Discovery of Therapies Against Neglected Diseases: A Drug Repurposing Approach

2019 ◽  
pp. 625-648 ◽  
Author(s):  
Carolina L. Belllera ◽  
María L. Sbaraglini ◽  
Lucas N. Alberca ◽  
Juan I. Alice ◽  
Alan Talevi
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Neglected Diseases ◽  
In Silico Modeling ◽  
Approved Drugs ◽  
Fda Approved Drugs

scholarly journals Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

2001 ◽  
Vol 75 (14) ◽  
pp. 6572-6583 ◽  
Author(s):  
Anuja Ghorpade ◽  
Raisa Persidskaia ◽  
Radhika Suryadevara ◽  
Myhanh Che ◽  
Xiao Juan Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Infection ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
De Novo ◽  
Mononuclear Phagocyte ◽  
Monocyte Migration ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory products and their interactions with neural cells. Viral infection and MP immune activation may affect leukocyte entry into the brain. One factor that influences central nervous system (CNS) monocyte migration is matrix metalloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial cells and affect the integrity of the neuropil extracellular matrix (ECM). To ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HIV-1-infected and/or immune-activated monocyte-derived macrophages (MDM) and human fetal microglia were examined for production of MMP-1, -2, -3, and -9. MMP expression increased significantly with MP differentiation. Microglia secreted high levels of MMPs de novo that were further elevated following CD40 ligand-mediated cell activation. Surprisingly, HIV-1 infection of MDM led to the down-regulation of MMP-9. In encephalitic brain tissue, MMPs were expressed within perivascular and parenchymal MP, multinucleated giant cells, and microglial nodules. These data suggest that MMP production in MP is dependent on cell type, differentiation, activation, and/or viral infection. Regulation of MMP expression by these factors may contribute to neuropil ECM degradation and leukocyte migration during HAD.

scholarly journals Evaluation of de novo transcriptome assemblies from RNA-Seq data

2014 ◽  
Author(s):  
Bo Li ◽  
Nathanael Fillmore ◽  
Yongsheng Bai ◽  
Mike Collins ◽  
James A Thomson ◽  
...  
Keyword(s):  
De Novo ◽  
Ground Truth ◽  
Rna Seq ◽  
De Novo Transcriptome ◽  
Model Based ◽  
Assembly Accuracy

RNA-Seq assembly facilitates the study of transcriptomes for species without sequenced genomes, but it is challenging to select the most accurate assembly in this context. To address this challenge, we developed a model-based score, RSEM-EVAL, for evaluating assemblies when the ground truth is unknown. Our experiments show that RSEM-EVAL correctly reflects assembly accuracy, as measured by REF-EVAL, a refined set of ground-truth-based scores that we also developed. With the guidance of RSEM-EVAL, we assembled the transcriptome of the regenerating axolotl limb; this assembly compares favorably to a previous assembly.

scholarly journals Tr1 cell immunotherapy promotes transplant tolerance via de novo Tr1 cell induction in mice and is safe and effective during acute viral infection

2018 ◽  
Vol 48 (8) ◽  
pp. 1389-1399 ◽  
Author(s):  
Tatiana Jofra ◽  
Roberta Di Fonte ◽  
Giuseppe Galvani ◽  
Mirela Kuka ◽  
Matteo Iannacone ◽  
...  
Keyword(s):  
Viral Infection ◽  
De Novo ◽  
Transplant Tolerance ◽  
Cell Immunotherapy ◽  
Acute Viral Infection ◽  
Cell Induction

scholarly journals Electroencephalographic Abnormalites in SARS-CoV-2 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Stephane Besnard ◽  
Clotilde Nardin ◽  
Elsa Lyon ◽  
Thomas Debroucker ◽  
Roxana Arjmand ◽  
...  
Keyword(s):  
Viral Infection ◽  
Retrospective Analysis ◽  
De Novo ◽  
Clinical Signs ◽  
Epileptic Seizures ◽  
Loss Of Consciousness ◽  
Eeg Abnormalities ◽  
History Of ◽  
Loss Of Contact ◽  
History Of Epilepsy

Viral infection with SARS-CoV-2 has a neurological tropism that may induce an encephalopathy. In this context, electroencephalographic exploration (EEG) is indicated as a diagnostic argument correlated with lumbar puncture, biology, and imaging. We performed a retrospective analysis of 42 patients explored by EEG and infected by COVID-19, according to the EEG abnormalities and clinical signs that motivated the examination. Confusion and epileptic seizures were the most common clinical indications, with 64% of the patients displaying these symptoms. The EEG was altered in 85% of the cases of confusion, in 57% of the cases of epileptic symptoms (general or focal seizure or prolonged loss of contact) and 20% of the cases of malaise or brief loss of consciousness. Nine EEG (21%) were in favor of an encephalopathy, two had de novo alterations in persistent consciousness and two had alterations in general states of confusion; one was very agitated and without history of epilepsy and combined eyelids clonia while a second one exhibited unconsciousness with left hemicorpus clonus. Two were being investigated for delayed awakening without sedation for more than 24 h. All of these patients were diagnosed COVID-19, some of them with associated mild to severe respiratory disorders. This work shows the interest of the EEG in exploring COVID-19 patients suffering from neurological or general symptoms looking for cerebral alteration.

Recent Drug-Repurposing-Driven Advances in the Discovery of Novel Antibiotics

2019 ◽  
Vol 26 (28) ◽  
pp. 5363-5388 ◽  
Author(s):  
Ananda Kumar Konreddy ◽  
Grandhe Usha Rani ◽  
Kyeong Lee ◽  
Yongseok Choi
Keyword(s):  
Drug Discovery ◽  
Bacterial Infections ◽  
De Novo ◽  
Genetic Disorder ◽  
Antibacterial Properties ◽  
Drug Repurposing ◽  
Global Public Health ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Novel Antibiotics

: Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information on potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever-increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016–2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, antiinflammatory, anti-malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity in its effective implications for inhibiting MDRBIs by repurposing existing drugs.

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