A promising approach in cancer therapy is to find ligands that directly bind ubiquitin (Ub) chains. However, finding molecules capable of tightly and specifically binding Ub chain is challenging given the range of Ub polymer lengths and linkages and their subtle structural differences. Upon generation of highly homogenous Ub chains for screening, De novo cyclic peptides were found that can tightly bind and specifically to K48-linked Ub chains. These cyclic peptides protected K48-linked Ub chains from deubiquitinating enzymes and prevented proteasomal degradation of Ub-tagged proteins. The cyclic peptides could enter cells, inhibit growth, and induce programmed cell death, opening new opportunities for therapeutic intervention.
- De novo cyclic peptides bind tightly to Lys48-linked Ub chains with great selectivity towards the chain length (mono, di and tetra-Ub) and type (Lys48 vs Lys63)
- These cyclic peptides can be rapidly modified to improve their drug properties.
Applications and Opportunities
- These modulators have potential to become a treatment for different cancer diseases similar to the the FDA-approved anti-cancer drugs in the ubiquitin system, yet with novel mechanism of action.