IMM / Synthetic Organic Chemistry
Rheumatoid arthritis (RA) is characterized by chronic inflammation in joint tissue. Conversion of peptidyl arginines to citrullines occurs during inflammation, thereby forming cyclic citrullinated peptides (CCPs). Autoreactive B cells recognize these CCPs with their unique B cell receptors (BCRs) and sustain inflammation by release of anti-citrullinated protein antibodies (ACPAs). We aim to selectively eliminate these autoreactive B cells in a Trojan horse-like strategy. The prodrug consists of an existing BCR signalling inhibitor conjugated to a synthetic CCP. Autoreactive BCRs uniquely recognize the CCP and upon internalisation the cell’s cathepsins release the BCR signalling inhibitor, thereby activating its cytotoxic properties.