ABSTRACT
Numerous bioactive peptides and their peptidomimetic analogs have been synthesized, and some are used in the clinic (1). Linear peptides composed of the natural amino acids are limited in their therapeutic value because their high degree of flexibility commonly leads to low binding affinity and a fast rate of degradation by proteases. Strategies to overcome these problems have led to a variety of molecules displaying very broad chemical diversity-ranging from constrained, cyclic peptide analogs through molecules having various nonpeptide links between amino acids all the way to molecules with chemical scaffolds that bear no resemblance to peptidic backbones (2). Yet success with protein-mimetic analogs (analogs that can disrupt protein-protein interactions) has not followed. This may be due, in part, to the limited conformation space that standard cyclization methods (disulfide, head-to-tail, or side chain-to-side chain) confer to the peptidic backbone. Peptor's backbone cyclization technology (3) enables the creation of large ensembles of conformationally constrained peptidomimetic analogs by bridging any two positions along their backbones through bridges of varying sizes and chemical compositions. Peptor uses this technology to generate large ensembles of structurally shaped compounds termed SCAPLs-small cyclic analogs of protein loops-which have the potential to disrupt protein-protein interactions. An example of a SCAPL is depicted in Fig. I.
