Unlike phosphorylation and dephosphorylation, there was no tool or drug to detect Pin1-catalyzed cis-transconformational changes after phosphorylation in the cell. Therapeutic antibodies are the most rapidly growing drug class due to their unprecedented efficacy and safety, but the current antibody drugs mainly recognize the primary rather than stereo structures of their target proteins located in the extracellular rather than intracellular space. We have developed innovative peptide chemistry to generate a new generation of stereo-specific antibodies able to detect and ablate intracellular cis- or trans Pin1 substrate conformations for discovering early disease mechanism, diagnostics and therapeutics (Cell 2012). Notably, our lab has discovered that whereas trans isomer is vital for brain function, cis P-tau231 causes and spreads neurodegeneration like a prion in AD, after brain injury or stroke (Cell 2012; Nature 2015; Nature Commun 2017; Science TM 2021). Others have confirmed cis P-tau231 as an extremely early blood biomarker for pre-clinical AD patients. Importantly, we have shown that cis P-tau231 can be effectively targeted by cis P-tau antibody in AD, TBI or stroke, with the clinical trials ongoing.
Dr. Lu Laboratory and Dr. Zhou Laboratory, Western University, 1400 Western Road, SDRI Room 107, London, Ontario N6G 2V4, Canada. The co-crystal structures of Pin1 and its inhibitors are generated by Shaunik Sharma using Pymol.
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