Abstract The recognition by Franz Hofmeister  and by Emil Fischer  that the structure of proteins is best represented by chains of amino-acids linked to each other through amide bonds, was preceded by the syntheses of the first simple peptide derivatives by Curtius  and later by Fischer . The challenge that led to these endeavors can be discerned throughout the history of organic chemistry: reproduction, or perhaps re-creation, of the work of nature. Subsequently, the aims of custom peptide synthesisbecame more pragmatic. Preparation of small, well-defined peptides turned out to be indispensable for the study of the specificity of proteolytic enzymes.
The synthetic peptides as substrates were models of complex proteins. In turn, the difficulties experienced in the synthesis of even such simple model compounds stimulated a sustained effort toward improvements in the methodology of custom peptide synthesis. With the discovery of biologically active peptides, the objectives of synthesis underwent a dramatic change.
Nonribosomal peptide synthetases (NRPSs) are large multienzyme machineries that assemble numerous peptides with large structural and functional diversity. These peptides include more than 20 marketed drugs, such as antibacterials (penicillin, vancomycin), antitumor compounds (bleomycin), and immunosuppressants (cyclosporine). Over the past few decades biochemical and structural biology studies have gained mechanistic insights into the highly complex assembly line of nonribosomal peptides. This Review provides state-of-the-art knowledge on the underlying mechanisms of NRPSs and the variety of their products along with detailed analysis of the challenges for future reprogrammed biosynthesis. Such a reprogramming of NRPSs would immediately spur chances to generate analogues of existing drugs or new compound libraries of otherwise nearly inaccessible compound structures.