ABSTRACT
The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , COVID-19 , Giant Cells , Pyrimidines/pharmacology , SARS-CoV-2/metabolism , Staurosporine/analogs & derivatives , A549 Cells , COVID-19/metabolism , Computational Biology , Drug Evaluation, Preclinical , Drug Repositioning , Giant Cells/metabolism , Giant Cells/virology , Humans , Staurosporine/pharmacologyABSTRACT
The COVID-19 disease led to an unprecedented health emergency, still ongoing worldwide. Given the lack of a vaccine or a clear therapeutic strategy to counteract the infection as well as its secondary effects, there is currently a pressing need to generate new insights into the SARS-CoV-2 induced host response. Biomedical data can help to investigate new aspects of the COVID-19 pathogenesis, but source heterogeneity represents a major drawback and limitation. In this work, we applied data integration methods to develop a Unified Knowledge Space (UKS) and used it to identify a new set of genes associated with SARS-CoV-2 host response, both in vitro and in vivo. Functional analysis of these genes reveals possible long-term systemic effects of the infection, such as vascular remodelling and fibrosis. Finally, we identified a set of potentially relevant drugs targeting proteins involved in multiple steps of the host response to the virus.
Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , COVID-19/genetics , COVID-19/physiopathology , COVID-19/virology , Genes, Viral , Humans , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , TranscriptomeABSTRACT
Long-term effects of Covid-19 disease are still poorly understood. However, similarities between the responses to SARS-CoV-2 and certain nanomaterials suggest fibrotic pulmonary disease as a concern for public health in the next future. Cross-talk between nanotoxicology and other relevant disciplines can help us to deploy more effective Covid-19 therapies and management strategies.