De novo design of nonpeptidic compounds targeting the interactions between interferon-alpha and its cognate cell surface receptor.
Type 1 interferons (IFN) bind specifically to the corresponding receptor, IFNAR. Agonists and antagonists for IFNAR have potential therapeutic value in the treatment of viral infections and systemic lupus erythematosus, respectively. Specific sequences on the surface of IFN, IFN receptor recognition peptides (IRRPs) mediate the binding and signal transduction when IFN interacts with IFNAR. Structural features of two such IRRPs, IRRP-1 and IRRP-3, were used as templates to design small molecule mimetics. In silico screening was used to identify the molecular structural features mimicking their surface characteristics. A set of 26 compounds were synthesized and their ability to interfere with IFN-IFNAR interactions was investigated. Two compounds exhibited antagonist activity, specifically, blocking IFN-inducible Stat phosphorylation Stat complex-DNA binding. Design principles revealed here pave the way toward a novel series of small molecules as antagonists for IFN-IFNAR interactions.
Bello
Angelica M
AM
Center for Molecular Design and Preformulations, Toronto General Research Institute, Toronto General Hospital, Toronto, ON M5G 2C4, Canada.
Bende
Tanushree
T
Wei
Lianhu
L
Wang
Xiaoyang
X
Majchrzak-Kita
Beata
B
Fish
Eleanor N
EN
Kotra
Lakshmi P
LP
D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D005663:Furans; D006146:Guanidines; D016898:Interferon-alpha; D010455:Peptides; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; D013876:Thiophenes; D053633:Receptor, Interferon alpha-beta; D004247:DNA