Ligandability Assessment of IL-1β by Integrated Hit Identification Approaches.

Area of Science:

• Immunology
• Medicinal Chemistry
• Drug Discovery

Background:

• Human interleukin-1β (IL-1β) is a key pro-inflammatory cytokine implicated in immune response dysregulation and inflammatory diseases.
• Targeting IL-1β signaling is a crucial strategy for developing novel therapeutics against inflammatory conditions.

Purpose of the Study:

• To discover and characterize novel small molecules and peptide binders that inhibit IL-1β activity.
• To identify new chemical entities that interfere with IL-1β-mediated signaling pathways.
• To explore potential therapeutic targets for covalent IL-1β antagonists.

Main Methods:

• Employed a multi-pronged approach combining fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening.
• Utilized diverse screening technologies to identify binders targeting distinct regions of IL-1β.
• Investigated the inhibitory potential of identified compounds against IL-1β and its interaction with the IL-1R1 receptor.

Main Results:

• Identified new chemical entities that bind to three distinct sites on IL-1β.
• Confirmed that all identified binders inhibit the interaction between IL-1β and the IL-1R1 receptor.
• Characterized lysine 103 of IL-1β as a promising residue for developing covalent IL-1β antagonists.

Conclusions:

• Multiple distinct chemical entities capable of inhibiting IL-1β signaling and IL-1R1 receptor interaction were discovered.
• The identified binders represent promising leads for the development of novel anti-inflammatory therapeutics.
• Lysine 103 presents a viable target for the design of covalent, low-molecular-weight IL-1β antagonists.