Poster Presentation 14th Australian Peptide Conference 2022

Optimization of phosphotyrosine peptides that target the SH2 domain of SOCS1 and block substrate ubiquitination (#113)

Hao Chen 1 2 , Yuntong Wu 1 2 , Kunlun Li 1 2 , Iain Currie 1 2 , Narelle Keating 1 2 , Farhad Dehkhoda 1 2 , Christoph Grohmann 1 2 , Jeffrey J Babon 1 2 , Sandra E Nicholson 1 2 , Brad E Sleebs 1 2
  1. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Suppressor of cytokine signaling 1 (SOCS1) has emerged as a potential therapeutic target in inflammatory and viral diseases. SOCS1 operates via its kinase inhibitory region, Src homology 2 (SH2) domain, and SOCS box to negatively regulate JAK/STAT pathway. We utilized native phosphotyrosine peptide substrates as a starting point to iteratively explore the requirement of each amino acid position to target the SOCS1-SH2 domain. We identified a series of phosphotyrosine peptides that have potent SOCS1 binding affinity with IC50 values ranging from 20 to 70 nM and greater than 100-fold selectivity against the closely related SOCS family proteins. The optimized phosphotyrosine peptide was able to stabilize SOCS1 in CETSA using cell lysates and inhibited SOCS1-mediated ubiquitination of a target substrate in a biochemical assay. Collectively, these data provide the framework to develop cell-permeable peptidomimetics that further investigate the potential of the SOCS1-SH2 domain as a therapeutic target in inflammatory and viral diseases.

 

  1. Chen, H.; Wu, Y.; Li, K.; Currie, I.; Keating, N.; Dehkhoda, F.; Grohmann, C.; Babon, J. J.; Nicholson, S. E.; Sleebs, B. E., Optimization of Phosphotyrosine Peptides that Target the SH2 Domain of SOCS1 and Block Substrate Ubiquitination. ACS Chem Biol 2022.