Improved synthesis of backbone and macrocyclic peptides: application to PKB, gp120 and integrase inhibitors

Cycloscan is a method that enables the fast discovery of peptido- and proteinomimetic molecules with desired pharmacological properties (e.g. metabolic stability, selectivity and intestinal permeability) [1]. Cycloscan is based on the synthesis of backbone cyclic focused libraries with conformational diversity, namely all the members of the library have the same sequence of the parent peptide or the active region of the protein. Screening of these libraries leads to the discovery of the desired peptido- or proteinomimetic. Some of the drawbacks of backbone cyclization, that limited its use, are synthetic problems derived from the cumbersome synthesis of protected building units, their incorporation into peptides and the cyclization step. We have developed (i) a facile, large scale synthesis of Allyl protected Gly building units (AGBU) (ii) the incorporation of AGBUs into backbone cyclic peptide using automatic SPPS (iii) facile synthesis of backbone to backbone cyclic peptides with on resin urea cyclization [2] (iii) microwave assisted solid phase synthesis of focused macrocyclic libraries with regio, stereo and conformational diversity. The synthetic improvements led to the discovery of potent substrate inhibitors of PKB, potent cell permeable inhibitors of integrase and an orally available macrocyclic entry inhibitor of HIV-1 replication. We hope that the synthetic improvements will facilitate the synthesis of backbone- and macrocyclic peptide- and proteinomimetics.