Volume 11 Issue 6, June 2015

We present a selection of papers published in Nature Chemical Biology over the past decade that reflect the diversity and excitement of chemical biology research.

The pharmaceutical industry continues to experience significant attrition of drug candidates during phase 2 proof-of-concept clinical studies. We describe some questions about the characteristics of protein targets and small-molecule drugs that may be important to consider in drug-discovery projects and could improve prospects for future clinical success.

Protein aggregation is a central hallmark of many neurodegenerative disorders, but the relationship of aggregate structural diversity to the resultant cellular cytotoxicity and phenotypic diversity has remained obscure. Recent advances in understanding the mechanisms of protein aggregation and their physiological consequences have been achieved through chemical biology approaches, such as rationally designed protein modifications and chemical probes, providing crucial mechanistic insights and promise for therapeutic strategies for brain disorders.

Agreeing on a precise definition of chemical biology has been a persistent challenge for the field. We asked a diverse group of scientists to “define chemical biology” and present a selection of responses.

Binding kinetics (BK) has an indispensable role in pharmacodynamics (PD). Incorporating slow BK into a mechanistic PD model is shown to have predictive value for in vitro cellular and in vivo animal antibacterial efficacy.

Boundaries between ordered and disordered membrane domains may be the site of HIV fusion protein insertion into its target membrane.

One-carbon metabolic pathways create new opportunities for metabolic engineering, but natural pathways have limitations in catalytic efficiency and interspecies transferability. Now a computationally designed enzyme, formolase, enables the construction of a synthetic metabolic pathway in Escherichia coli for assimilation of formate into a glycolytic intermediate in only five reaction steps.

This Perspective discusses recent advances in high-throughput omics approaches such as proteomic and interactome profiling and genetic perturbations that allow the identification and alterations of cell signaling networks.

The use of a presumed chemical intermediate in the mechanism of enoyl thioester reductase enables the identification of the long-sought proton donor and the rational redesign of enzyme stereoselectivity.

The natural product didemnin B inhibits PPT1 and the antiapoptotic protein Mcl-1 in particular types of cancer cells containing a unique genetic profile that correlates with drug sensitivity.

Retinoid isomerase is a critical enzyme in the conversion of retinyl esters to 11-cis-retinol, a key step in the regeneration of visual pigments that mediate light perception. Structural, biochemical and modeling data using substrate analogs explain how this unusual reaction proceeds.

Drug-target residence time is viewed as a predictor of the clinical efficacy of small-molecule drugs. A pharmacodynamic model, taking into account the target binding kinetics of antibacterial compounds, leads to accurate predictions of cellular and in vivo efficacies of the inhibitors.

Fusion of HIV with target membranes via the HIV fusion peptide requires phase separation among lipids as well as phase heterogeneity because the fusion is biased toward the boundary between regions of ordered (so-called rafts) and disordered lipids.

Protein methyltransferase PRMT5 symmetrically dimethylates arginine residues in proteins, including histones, and has been associated with tumorigenesis. The identification of EPZ015666 as a potent chemical probe of PRMT5 could promote understanding of the role of PRMT5 in human disease both in cells and in vivo.

With the June 2015 issue, Nature Chemical Biologycelebrates 10 years of serving the chemical biology community. In honor of this anniversary, we are presenting a collection of articles that highlights the scientific accomplishments and promising future of chemical biology.