title: Small molecule mimetics of an interferon-α receptor interacting domain.
abstract: Small molecules that mimic IFN-α epitopes that interact with the cell surface receptor, IFNAR, would be useful therapeutics. One such 8-amino acid region in IFN-α2, designated IRRP-1, was used to derive 11 chemical compounds that belong to 5 distinct chemotypes, containing the molecular features represented by the key residues Leu30, Arg33, and Asp35 in IRRP-1. Three of these compounds exhibited potential mimicry to IRRP-1 and, in cell based assays, as predicted, effectively inhibited IFNAR activation by IFN-α. Of these, compound 3 did not display cell toxicity and reduced IFN-α-inducible STAT1 phosphorylation and STAT-DNA binding. Based on physicochemical properties' analyses, our data suggest that moieties with acidic pKa on the small molecule may be a necessary element for mimicking the carboxyl group of Asp35 in IRRP-1. Our data confirm the relevance of this strategy of molecular mimicry of ligand-receptor interaction domains of protein partners for small molecule drug discovery.
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Toronto General Research Institute, Toronto, Ontario M5G 2M1, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Bello
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Toronto General Research Institute, Toronto, Ontario M5G 2M1, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2M1, Canada.
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Noruê
authors.initials: N
authors.lastname: Salum
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333 031, India.
authors.forename: Meena K
authors.initials: MK
authors.lastname: Purohit
authors.affiliation: Toronto General Research Institute, Toronto, Ontario M5G 2M1, Canada; Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.affiliation: Center for Molecular Design and Preformulations, University Health Network, Toronto, Ontario M5G 1L7, Canada; Toronto General Research Institute, Toronto, Ontario M5G 2M1, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: lkotra@uhnres.utoronto.ca.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D002460:Cell Line / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000939:Epitopes; D016898:Interferon-alpha; D010455:Peptides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D054852:Small Molecule Libraries; D053633:Receptor, Interferon alpha-beta; D001224:Aspartic Acid
keywords: IFN-α receptor; Interferon; Peptidomimetics