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

Human interleukin-1β (IL-1β) is a pro-inflammatory
cytokine that plays a critical role in the regulation of the immune
response and the development of various inflammatory diseases. In
this publication, we disclose our efforts toward the discovery of
IL-1β binders that interfere with IL-1β signaling. To
this end, several technologies were used in parallel, including fragment-based
screening (FBS), DNA-encoded library (DEL) technology, peptide discovery
platform (PDP), and virtual screening. The utilization of distinct
technologies resulted in the identification of new chemical entities
exploiting three different sites on IL-1β, all of them also
inhibiting the interaction with the IL-1R1 receptor. Moreover, we
identified lysine 103 of IL-1β as a target residue suitable
for the development of covalent, low-molecular-weight IL-1β
antagonists.