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1.
Sci Rep ; 11(1): 6725, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762619

RESUMO

The recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/metabolismo , Mineração de Dados/métodos , Fator de Transcrição AP-1/metabolismo , Animais , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , COVID-19/epidemiologia , COVID-19/genética , Chlorocebus aethiops , Bases de Dados Genéticas , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Terapia de Alvo Molecular , Pandemias , SARS-CoV-2/isolamento & purificação , Células Vero
2.
Nat Biotechnol ; 39(6): 747-753, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33623157

RESUMO

Computational approaches for drug discovery, such as quantitative structure-activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies.


Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Ensaios de Triagem em Larga Escala/métodos , SARS-CoV-2/efeitos dos fármacos , COVID-19/genética , COVID-19/virologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , SARS-CoV-2/patogenicidade
3.
bioRxiv ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32766591

RESUMO

The recent global pandemic caused by the new coronavirus SARS-CoV-2 presents an urgent need for new therapeutic candidates. While the importance of traditional in silico approaches such as QSAR in such efforts in unquestionable, these models fundamentally rely on structural similarity to infer biological activity and are thus prone to becoming trapped in the very nearby chemical spaces of already known ligands. For novel and unprecedented threats such as COVID-19 much faster and efficient paradigms must be devised to accelerate the identification of new chemical classes for rapid drug development. Here we report the development of a new biological activity-based modeling (BABM) approach that builds on the hypothesis that compounds with similar activity patterns tend to share similar targets or mechanisms of action. In BABM, compound activity profiles established on massive scale across multiple assays are used as signatures to predict compound activity in a new assay or against a new target. We first trained and validated this approach by identifying new antiviral lead candidates for Zika and Ebola based on data from ~0.5 million compounds screened against ~2,000 assays. BABM models were then applied to predict ~300 compounds not previously reported to have activity for SARS-CoV-2, which were then tested in a live virus assay with high (>30%) hit rates. The most potent compounds showed antiviral activities in the nanomolar range. These potent confirmed compounds have the potential to be further developed in novel chemical space into new anti-SARS-CoV-2 therapies. These results demonstrate unprecedented ability using BABM to predict novel structures as chemical leads significantly beyond traditional methods, and its application in rapid drug discovery response in a global public health crisis.

4.
Drug Discov Today ; 24(12): 2341-2349, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585169

RESUMO

The National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC), a comprehensive collection of clinically approved drugs, was made a public resource in 2011. Over the past decade, the NPC has been systematically profiled for activity across an array of pathways and disease models, generating an unparalleled amount of data. These data have not only enabled the identification of new repurposing candidates with several in clinical trials, but also uncovered new biological insights into drug targets and disease mechanisms. This retrospective provides an update on the NPC in terms of both successes and lessons learned. We also report our efforts in bringing the NPC up-to-date with drugs approved in recent years.


Assuntos
Aprovação de Drogas , Reposicionamento de Medicamentos , National Center for Advancing Translational Sciences (U.S.)/tendências , Desenvolvimento de Medicamentos/tendências , Humanos , Estados Unidos
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