PerspectiveViewpoint: COVID-19

Rapid repurposing of drugs for COVID-19

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Science  22 May 2020:
Vol. 368, Issue 6493, pp. 829-830
DOI: 10.1126/science.abb9332

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  • SARS and HIV inhibitory peptides with therapeutic potential against Covid-19
    • Babu V. Bassa, Professor, Department of Environmental Toxicology, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, L
    • Other Contributors:
      • Rao M. Uppu, Professor, Department of Environmental Toxicology, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, L

    In the article “Rapid repurposing of drugs for COVID-19” (1) the authors have done a great job in highlighting approved drugs for their potential use against Covid-19. However, one very relevant class of drugs not covered by the authors is the “fusion inhibitors”. For example, the fusion inhibitory peptide T20 (enfuvirtide), approved by the FDA for AIDS, is homologous to the SARS-CoV-2 fusioncore. Both the HIV and coronaviruses infect cells using similar fusion mechanisms. In COVID-19, the spike glycoprotein fuses to the plasma membrane prior to internalization which is similar to the fusion of HIV via the envelope protein gp41. In both cases, fusion is mediated by two hydrophobic regions of the envelope molecules designated as HR1 and HR2. Inhibitory peptides homologous to these regions inhibit fusion through competition. From the published literature we have identified 101 peptides that had undergone in vitro testing during the years of the SARS-CoV outbreak, and using our alignment-free software (2) we have found that 36 of these peptides are present as identical motifs in the SARS-CoV-2 spike glycoprotein. Further, the respective authors reported only four of the 36 peptides to have significant antiviral activity at acceptable concentrations. Additionally, a recent study directly on SARS-CoV-2 identified another active peptide (3). Interestingly, four of the five active peptides have a spike glycoprotein sequence held in common: “ginasvvniqkeidrlnevaknlneslidl...

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    Competing Interests: None declared.
  • Repurposing of drugs that target pathobiology for the treatment of COVID-19
    • Paul A. Insel, Professor, University of California San Diego
    • Other Contributors:
      • Rohit Loomba, Professor, University of California San Diego
      • Krishna Sriram, Postdoctoral Scholar, University of California San Diego

    Guy et al [1] described potential targets for the treatment of COVID-19, including evaluation of approved drugs via use of in silico and “wet lab” approaches (e.g., Gordon et al [2]). Because approved drugs have well-defined pharmacokinetics, pharmacodynamics and adverse effects, they can be rapidly repurposed following evaluation of efficacy and safety in prospective randomized controls trials (RCTs).

    Discussions of repurposing, including by Guy et al [1], generally emphasize approaches to directly inhibit viral entry and replication. In addition, consideration of drugs for repurposing should include ones that reduce COVID-19 pathobiology, by targeting biochemistry and physiology dysregulated by COVID-19 in host cells. A key example is imbalance in the Renin-Angiotensin-Aldosterone System (RAAS), mediated by peptides derived from Angiotensin Converting Enzymes-1 and -2 (ACE1/ACE2) [3]. These enzymes catalyze, respectively, conversion of Angiotensin-I to Antiotensin-2 (Ang-2) and to other peptides (e.g., Ang (1-7)), whose actions oppose those of Ang-2 mediated by Angiotensin receptor-1 (AGTR-1) [3]. Binding of SARS-CoV-2 to ACE2 blunts activity and expression. The resultant decrease in Ang (1-7) and increase in Ang-2 actions induces injury, especially in the lungs and heart, leading to cytokine storm and multi-organ failure [3].

    Many approved drugs target RAAS components, including ACE1 inhibitors (ACEIs) and AGTR-1 antagonists (angiotensin receptor blocke...

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    Competing Interests: KS has no conflicts of interest. RL serves as a consultant or advisory board member for Arrowhead Pharmaceuticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse bio, GNI, GRI Bio, Intercept, Ionis, Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Sanofi, Siemens, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, pH Pharma, Prometheus, and Siemens. He is also co-founder of Liponexus, Inc PAI is not currently but within the past 3 years has served as a consultant or received research support from Merck, Pfizer, and Bristol Myers Squibb.

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