The 4 pre-selected libraries were then mixed, modified by KYL to afford Malins-style bicycles and Raj-style bicycles, selected on NS3aH1, and sequences eluted by grazoprevir were analyzed by NGS. As a control, selection was also performed using mixed libraries without any modification (Figure , b, Figure ). NGS analysis of reshaped library panning revealed two distinct landscapes: The first population showed enrichment in unmodified libraries but they 'dropped out' and exhibited less or no enrichment in the selection of reshaped libraries, suggesting no tolerance to chemical modifications (Figure , Tables S6); the second population remained the enrichment after reshaping, and over 80% sequences beared the HXDMT motif, indicating its endurance to changes in peptide geometry caused by chemical modifications (Table ). Further analysis on 4 disulfide ring architectures revealed that, in top 50 SX3CX9C type peptides, 30/50 'dropped out' after bicyclization with KYL linker and 20/50 tolerated reshaping to bicyclic peptides (Table , Figure ), whereas in top 50 SCX12C type peptides, only 12/50 'dropped out' after modification and 38/50 tolerated reshaping to bicyclic peptides (Table ).