Commentary in 2013

Peptides fulfill many roles in immunology, yet none are more important than their role as immunogenic epitopes driving the adaptive immune response, our ultimate bulwark against infectious disease. Peptide epitopes are mediated primarily by their interaction with major histocompatibility complexes (T-cell epitopes) and antibodies (B-cell epitopes). As pathogen genomes continue to be revealed, both experimental and computational epitope mapping are becoming crucial tools in vaccine discovery^1,2. Immunoinformatics offers many tools, techniques and approaches for in silico epitope characterization, which is capable of greatly accelerating epitope design.

Genetic code expansion for synthesis of proteins containing noncanonical amino acids is a rapidly growing field in synthetic biology. Creating optimal orthogonal translation systems will require re-engineering central components of the protein synthesis machinery on the basis of a solid mechanistic biochemical understanding of the synthetic process.

The recent development of a broad range of biocatalysts that can be applied in organic synthesis has brought into focus the need to rethink the way in which organic target molecules might be constructed in the future. To aid synthetic chemists in identifying where biocatalysts might be usefully applied, we propose that guidelines and rules for 'biocatalytic retrosynthesis' be developed and that this new approach be embedded in the future training and education of organic chemists.

Small-molecule phenotypic screening has high potential in the discovery of new chemical probes and new biological small-molecule targets. This commentary will discuss the basic principles underlying the design of phenotypic screens and propose some guidelines to facilitate the discovery of small molecules from phenotypic screens.

Providing chemical matter to modulate newly identified biological targets—as well as pre-existing but chemically intractable ones—remains a challenge in the discovery of therapeutics. Here, we discuss opportunities for synthetic chemists to make a direct impact in addressing targets that are considered 'undruggable'.

Fully profiled chemical probes are essential to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation. We believe that by developing a 'chemical probe tool kit', and a framework for its use, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation as practiced currently.

Chemical probes are critical tools for elucidating the biological functions of proteins and can lead to new medicines for treating disease. The pharmacological validation of protein function requires verification that chemical probes engage their intended targets in vivo. Here we discuss technologies, both established and emergent, for measuring target engagement in living systems and propose that determining this parameter should become standard practice for chemical probe and drug discovery programs.