Volume 6 Issue 12, December 2010

With insights from a panel of experts, the Nature Chemical Biology editors examine the evolution and current era of chemical biology.

Some of the most celebrated triumphs of chemical biology are molecularly targeted therapeutics to combat human disease. However, a grand challenge looms as informative diagnostic strategies must be developed to realize the full impact of these promising pharmaceutical agents.

Engineering biosynthetic pathways to natural products is a challenging endeavor that promises to provide new therapeutics and tools to manipulate biology. Information-guided design strategies and tools could unlock the creativity of a wide spectrum of scientists and engineers by decoupling expertise from implementation.

The synthesis and biological annotation of small molecules from underexplored chemical space will play a central role in the development of drugs for challenging targets currently being identified in frontier areas of biological research such as human genetics.

Post-transcriptional RNA modifications can be dynamic and might have functions beyond fine-tuning the structure and function of RNA. Understanding these RNA modification pathways and their functions may allow researchers to identify new layers of gene regulation at the RNA level.

In the postsequencing era, chemical biology is uniquely situated to investigate genomic DNA alterations arising through epigenetic modifications, genetic rearrangements or active mutation. These transformations significantly expand nature's diversity and may profoundly alter our view of DNA's coding potential.

Chemical biology is now able to discover molecules that manipulate virtually any biological target or process. It remains a grand challenge to leverage these molecules into useful probes that can be used to address unsolved problems in biology.

Rationally designing new strategies to control the human immune response stands as a key challenge for the scientific community. Chemical biologists have the opportunity to address specific issues in this area that have important implications for both basic science and clinical medicine.

Variations between single members of a bacterial population can lead to antibiotic resistance that is not gene based. The future of effective infectious disease management might depend on a better understanding of this phenomenon and the potential to manipulate both it and microbial population dynamics in general.

Hyper-performing whole-cell catalysts are required for the renewable and sustainable production of petrochemical replacements. Chassis cells—self-replicating minimal machines that can be tailored for the production of specific chemicals—will provide the starting point for designing these hyper-performing 'turbo cells'.

The ability to alter cell identity with small molecules represents a powerful approach to restore biological function lost because of cellular deficiency. Developing this capability through advances in chemical biology could have an enormous impact on human health.

Although members of the Hsp70-DnaK family of heat shock proteins are involved in nearly all aspects of cell physiology, some mechanistic details of their mode of action remain obscure. A new substrate helps establish DnaK as an unfoldase that requires as little as five ATP molecules to drive the refolding of one protein.

Conjugation of a known, mechanism-based glycosidase inhibitor to sensitive fluorophores yielded unexpectedly potent and selective probes for quantifying active lysosomal glucocerebrosidase. These conjugates could prove to be invaluable tools for diagnosing and studying Gaucher disease.

The glucose-based polymer cellulose is of great biological and economical importance; however, little is known about how cellulose is synthesized. Now, structural estimates of one of the cellulose-synthesizing subunits in the bacterium Acetobacter xylinum help to explain the extrusion of the newly synthesized glucan chains.

A new method to monitor interactions between cell surface proteins reveals that interaction of the neuronal cell surface adhesion proteins neurexin and neuroligin is increased at synapses during a stimulus or developmental activity. This increased activity-dependent surface density of neurexin–neuroligin complexes is subsequently required for maturation of synapses.

The antiviral S-acyl-2-mercaptobenzamide thioester ejects an essential coordinated zinc ion from and induces aggregation and dysfunction of the HIV-1 nucleocapsid protein NCp7 via repetitive intracellular enzymatic acyl transfers, dependent on acetyl-CoA.

Free-energy molecular dynamics simulations and high-resolution structural analysis of the c-ring of the F₁F_o ATPase rotary motor, which mediates ion translocation, suggest conformational flexibility and reversible ion binding in the c-subunits, in an environment mimicking the a-subunit.

Expression of a Huntington's-disease variant of huntingtin protein causes accumulation of the chaperone protein disulfide isomerase. This protein is the target of compounds obtained from screening for those that can alleviate cell death promoted by the mutant huntingtin, and represents a new connection between protein misfolding and cell death.

Fluorescent high-affinity activity-based probes used to monitor the activity and presence of active glucocerebrosidase in vitro and in vivo help in understanding Gaucher disease and its treatment with pharmacological chaperones.

Protein chaperones help misfolded proteins reach their native state, but the necessarily unstable substrates have complicated the analysis of chaperone function. A stable misfolded luciferase substrate now allows the determination of traditional enzyme parameters for the DnaK system, demonstrating that five cycles of unfolding and release are needed for one successful refolding event.

This special issue presents a collection of articles exploring the foundations of chemical biology, reviewing some of the major technical and conceptual advances of the last decade, and imagining the future of this vibrant field.