Selinexor and COVID-19: The Neglected Warden

Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV–host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.

Significance To successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that the viral accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able to inhibit STAT1 nuclear translocation to block IFN signaling. In this study, we report that Orf6 localizes at the nuclear pore complex (NPC) where it binds directly to the Nup98-Rae1 complex to target the nuclear import pathway and mediate this inhibition. A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines.

Background The severe acute respiratory syndrome (SARS) coronavirus-2 is a novel coronavirus belonging to the family Coronaviridae and is now known to be responsible for the outbreak of a series of recent acute atypical respiratory infections originating in Wuhan, China. The disease caused by this virus, termed coronavirus disease 19 or simply COVID-19, has rapidly spread throughout the world at an alarming pace and has been declared a pandemic by the WHO on March 11, 2020. In this review, an update on the pathophysiology, clinical presentation and the most recent management strategies for COVID-19 has been described. Materials and Methods A search was conducted for literature and various articles/case reports from 1997 to 2020 in PUBMED/MEDLINE for the keywords coronavirus, SARS, Middle East respiratory syndrome and mRNA virus. Results and Conclusions COVID-19 has now spread globally with increasing morbidity and mortality among all populations. In the absence of a proper and effective antibody test, the diagnosis is presently based on a reverse-transcription PCR of nasopharyngeal and oropharyngeal swab samples. The clinical spectrum of the disease presents in the form of a mild, moderate or severe illness. Most patients are either asymptomatic carriers who despite being without symptoms have the potential to be infectious to others coming in close contact, or have a mild influenza-like illness which cannot be differentiated from a simple upper respiratory tract infection. Moderate and severe cases require hospitalisation as well as intensive therapy which includes non-invasive as well as invasive ventilation, along with antipyretics, antivirals, antibiotics and steroids. Complicated cases may require treatment by immunomodulatory drugs and plasma exchange therapy. The search for an effective vaccine for COVID-19 is presently in full swing, with pharmaceutical corporations having started human trials in many countries.