Design, synthesis and structure of peptides and proteins

Proteins constitute the working machinery and structural support of all organisms. Understanding the molecular basis of a disease, namely where and how the protein network fails, is crucial for developing a therapeutic strategy. The breakthrough concept that proteins function as a contact network rather than as independent agents is not only one of the most important advances in our comprehension of living systems, but it also translates into a new era in drug discovery. The few reported examples of diseases caused by ‘impolite’ social behaviour of proteins are merely the tip of the iceberg. Therapeutic intervention through molecules designed to selectively modulate the strength and specificity of protein–protein interactions is becoming a reality. Mass spectrometry (MS), nuclear magnetic resonance (NMR) and atomic force microscopy (AFM) are emerging as privileged tools to study the structure of proteins and the complex molecular recognition events that take place in protein-protein interactions, and the interaction of designed ligands – potential new drugs – with protein surfaces. However, the efficient use of these spectroscopic tools is still hampered by numerous difficulties. Regarding MS, the high dynamic range of protein concentrations in living organisms is one of the major challenges in contemporary proteomics. In structure-based drug design, a previous knowledge of the 3D structure of the therapeutic target is mandatory. When this target is a high molecular weight protein, the use of NMR to determine the structure is not possible due to the following two problems associated with this high molecular weight: i) crowding of spectral signals; and ii) fast magnetic relaxation with the subsequent loss of sensitivity. Finally, in amyloid diseases, the study of molecular interactions by AFM or other techniques is strongly hampered by the strong tendency of amyloid proteins to self-assemble. Design, synthesis and structure of peptides and proteins Ernest Giralt