Targeted chemotherapeutic drug discovery enabled by direct screening of peptide-drug conjugate libraries

• Applicant: Dr. Yen-Chun Lee
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413623402

• Final Report Year: 2021

Final Report Abstract

For the development of peptide-based therapeutics, the SAR of the peptide sequence is critical for downstream optimization. Ms. Ye and I tried to streamline the hot-spot identification process and obtain higher-order SAR on a given peptide hit. In our deep alanine scanning platform, we offered a high-throughput strategy to study a broad alanine tolerance landscape for the peptide-protein complexes and discovered a new binding modality with multi-alaninesubstituted peptides. With the platform, we can perform the binder maturation toward the newly discovered Pt(IV)-peptide conjugate by replacing nonessential residuals and ultimately enhancing the biophysical properties.

Publications

• Discovery of High Affinity Peptide Binders for the SARS-CoV-2 Spike Protein, ACS Cent. Sci. 2021, 7, 156
  Pomplun, Sebastian; Jbara, Muhammad; Quartararo, Anthony J.; Zhang, Genwei; Brown, Joseph S.; Lee, Yen-Chun; Ye, Xiyun; Hanna, Stephanie & Pentelute, Bradley L.
  
• Platinum(IV) Prodrug – Perfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain, J. Med. Chem. 2020, 63, 6741
  Fadzen, Colin M.; Wolfe, Justin M.; Zhou, Wen; Cho, Choi-Fong; von Spreckelsen, Niklas; Hutchinson, Kathryn T.; Lee, Yen-Chun; Chiocca, E. Antonio; Lawler, Sean E.; Yilmaz, Omer H.; Lippard, Stephen J. & Pentelute, Bradley L.