Minimization of Proteins by Random Fragmentation and Selection

Protein-protein interactions are involved in most biological processes and are an important target for drug design. Over the past decade, there has been an increased interest in the design of small molecules that mimic functional epitopes in protein-protein interactions. However, the design of small molecules that disrupt protein-protein interactions remains a considerable challenge (1 ,2 ). Progress has been achieved towards minimizing proteins into significantly smaller polypeptides that retain the ability to bind a partner protein (3 –5 ). These mini-proteins represent a potential intermediate step between proteins and small molecules, and thus may facilitate the development of drugs targeted to protein-protein interfaces (6 ). Protein minimization has been achieved by both rational and combinatorial approaches and a large collection of proteins have now been minimized (3 ,7 –9 ).