Understanding COVID-19 Pathogenesis: A Drug-Repurposing Effort to Disrupt Nsp-1 Binding to Export Machinery Receptor Complex

Abstract

Non-structural protein 1 (Nsp1) is a virulence factor found in all beta coronaviruses (b-CoVs). Recent studies have shown that Nsp1 of SARS-CoV-2 virus interacts with the nuclear export receptor complex, which includes nuclear RNA export factor 1 (NXF1) and nuclear transport factor 2-like export factor 1 (NXT1). The NXF1–NXT1 complex plays a crucial role in the transport of host messenger RNA (mRNA). Nsp1 interferes with the proper binding of NXF1 to mRNA export adaptors and its docking to the nuclear pore complex. We propose that drugs targeting the binding surface between Nsp1 and NXF1–NXT1 may be a useful strategy to restore host antiviral gene expression. Exploring this strategy forms the main goals of this paper. Crystal structures of Nsp1 and the heterodimer of NXF1–NXT1 have been determined. We modeled the docking of Nsp1 to the NXF1–NXT1 complex, and discovered repurposed drugs that may interfere with this binding. To our knowledge, this is the first attempt at drug-repurposing of this complex. We used structural analysis to screen 1993 FDA-approved drugs for docking to the NXF1–NXT1 complex. The top hit was ganirelix, with a docking score of −14.49. Ganirelix competitively antagonizes the gonadotropin releasing hormone receptor (GNRHR) on pituitary gonadotrophs, and induces rapid, reversible suppression of gonadotropin secretion. The conformations of Nsp1 and GNRHR make it unlikely that they interact with each other. Additional drug leads were inferred from the structural analysis of this complex, which are discussed in the paper. These drugs offer several options for therapeutically blocking Nsp1 binding to NFX1–NXT1, which may normalize nuclear export in COVID-19 infection.

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1

“…As described in previous sections, the multifunctional SARS-CoV-2 Nsp1 interacts directly with the NXF1 and NXT1 proteins of the nuclear pore complex disrupting the nuclear mRNA export machinery and, therefore, inhibiting host gene expression ( Zhang et al., 2021 ). The e-Drug3D database, which contained around 2,000 Food and Drug Administration (FDA)-approved drugs, was used to dock to the structure of the NXF1/NXT1-Nsp1 complex to identify compounds that interfere with the binding of SARS-CoV-2 Nsp1 with NXF1/NXT1 ( Vasudevan and Baraniuk, 2021 ). In this in silico study, the top identified hit was ganirelix, which competitively antagonizes the gonadotropin releasing hormone receptor (GNRHR) ( Vasudevan and Baraniuk, 2021 ).…”

“…The e-Drug3D database, which contained around 2,000 Food and Drug Administration (FDA)-approved drugs, was used to dock to the structure of the NXF1/NXT1-Nsp1 complex to identify compounds that interfere with the binding of SARS-CoV-2 Nsp1 with NXF1/NXT1 ( Vasudevan and Baraniuk, 2021 ). In this in silico study, the top identified hit was ganirelix, which competitively antagonizes the gonadotropin releasing hormone receptor (GNRHR) ( Vasudevan and Baraniuk, 2021 ). However, authors did not carry out in vitro experimental tests to confirm the antiviral effect of this compound against SARS-CoV-2 ( Vasudevan and Baraniuk, 2021 ).…”

“…In this in silico study, the top identified hit was ganirelix, which competitively antagonizes the gonadotropin releasing hormone receptor (GNRHR) ( Vasudevan and Baraniuk, 2021 ). However, authors did not carry out in vitro experimental tests to confirm the antiviral effect of this compound against SARS-CoV-2 ( Vasudevan and Baraniuk, 2021 ).…”