Biphenyl-dihydrothiazole-cyclized peptide libraries for peptide ligand and drug discovery

Utilizing diverse organic crosslinkers for cyclization has proven to be an effective approach to creating peptide libraries, enabling the rapid discovery of functional peptides. Existing crosslinkers usually provide a tiny and flexible molecular scaffold to constrain peptide conformations, leading to larger cyclic peptides retaining a high degree of flexibility. Moreover, the limited structural impact of the crosslinkers undermines the feasibility of diversifying cyclic peptide structures by varying the types of crosslinker scaffolds. These limitations hamper the robustness of various cyclic peptide libraries for ligands and drug discovery and development. Herein, we present a unique crosslinker featuring a bulky and rigid biphenyl-dihydrothiazole (BDT) scaffold for the rapid and biocompatible cyclization of linear peptides. This scaffold was used to construct phage display BDT-cyclic peptide libraries, enabling the effective identification of cyclic peptide binders with low-nanomolar binding affinity toward BCL-X_L, a protein target with potential for cancer therapy. Thus, this study introduces a novel method for constructing cyclic peptide libraries with rigidly constrained and diverse structures, offering a promising avenue for the de novo discovery of cyclic peptide ligands and drugs.