title: Small Molecule Agonists for the Type I Interferon Receptor: An In Silico Approach.
abstract: Type I interferons (IFNs) exhibit broad-spectrum antiviral activity, with potential utility against emerging acute virus infections that pose a threat to global health. Recombinant IFN-αs that have been approved for clinical use require cold storage and are administered through intramuscular or subcutaneous injection, features that are problematic for global distribution, storage, and administration. Cognizant that the biological potency of an IFN-α subtype is determined by its binding affinity to the type I IFN receptor, IFNAR, we identified a panel of small molecule nonpeptide compounds using an in silico screening strategy that incorporated specific structural features of amino acids in the receptor-binding domains of the most potent IFN-α, IFN alfacon-1. Hit compounds were selected based on ease of synthesis and formulation properties. In preliminary biological assays, we provide evidence that these compounds exhibit antiviral activity. This proof-of-concept study validates the strategy of in silico design and development for IFN mimetics.
authors.affiliation: 1 Center for Molecular Design and Preformulations , Toronto, Canada .|2 Toronto General Research Institute, University Health Network , Toronto, Canada .|3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada .
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.affiliation: 1 Center for Molecular Design and Preformulations , Toronto, Canada .|2 Toronto General Research Institute, University Health Network , Toronto, Canada .|3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada .
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Bello
authors.affiliation: 2 Toronto General Research Institute, University Health Network , Toronto, Canada .
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.affiliation: 1 Center for Molecular Design and Preformulations , Toronto, Canada .|4 Federal University of Paraná , Paraná, Brazil .
authors.forename: Noruê
authors.initials: N
authors.lastname: Salum
authors.affiliation: 1 Center for Molecular Design and Preformulations , Toronto, Canada .|2 Toronto General Research Institute, University Health Network , Toronto, Canada .
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Lewis
authors.affiliation: 1 Center for Molecular Design and Preformulations , Toronto, Canada .|2 Toronto General Research Institute, University Health Network , Toronto, Canada .|3 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Canada .
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
authors.affiliation: 2 Toronto General Research Institute, University Health Network , Toronto, Canada .|5 Department of Immunology, Faculty of Medicine, University of Toronto , Toronto, Canada .
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D004686:Encephalomyocarditis virus / Q000187:drug effects* / Q000254:growth & development; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D053633:Receptor, Interferon alpha-beta / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D000998:Antiviral Agents; C507964:IFNAR1 protein, human; D016898:Interferon-alpha; D008024:Ligands; D057786:Peptidomimetics; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D053633:Receptor, Interferon alpha-beta; C050739:interferon alfacon-1