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

• Platinum(IV) Prodrug – Perfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain, J. Med. Chem. 2020, 63, 6741
  C. M. Fadzen, J. M. Wolfe, W. Zhou, C.-F. Cho, N. von Spreckelsen, K. T. Hutchinson, Y.-C. Lee, E. A. Chiocca, S. E. Lawler, O. H. Yilmaz, S. J. Lippard, B. L. Pentelute
  (See online at https://doi.org/10.1021/acs.jmedchem.0c00022)
• Discovery of High Affinity Peptide Binders for the SARS-CoV-2 Spike Protein, ACS Cent. Sci. 2021, 7, 156
  S. Pomplun, M. Jbara, A. Quartararo, G. Zhang, J. Brown, Y.-C. Lee, X. Ye, S. Hanna, B. L. Pentelute
  (See online at https://doi.org/10.1021/acscentsci.0c01309)