Protease-inhibitor Synthesis - A Demanding Test Case for Polymer Reagents

Protease-inhibitor Synthesis - A Demanding Test Case for Polymer Reagents 

The development of protease inhibitors faces several serious challenges. First, high affinity is demanded. Addressing a single protease in the presence of many others expressed in the human organism is, however, an even more difficult task (Box 15). 

For many of the prominent inhibitor families (Fig. 3.6.1, Boxes 12 and 13), the available synthetic strategies do not fulfil these requirements. In the synthesis of peptide aldehydes, e.g., the parallel synthesis of variable structures without race-mization is an unsolved problem. The same applies to the synthesis of many peptide isosteres such as the norstatines or the l,3-diamino-2-propanols. Typically, combinatorial variation of the N-terminal and C-terminal positions can be easily attained. The side chain of the isosteric building block itself and its stereochemistry can, however, currently be varied only by a synthetic effort this excludes versatile variation of the central inhibitory element. 

developing diversity-oriented methods for construction of isosteric building blocks will make an important contribution to propelling protease inhibitor research. 

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