Unpredicted drug toxicities remain a leading cause of attrition in clinical trials and are a major complication of drug therapy. Although the underlying causes of adverse drug reactions are often unknown, many have been attributed to the formation of chemically reactive drug metabolites (CRMs) and their covalent binding to off-targets. In their Review, Park and colleagues discuss the current understanding of the potential of compounds to generate CRMs and they analyse the methods available for detecting and minimizing their formation during drug development. However, drugs that selectively bind covalently to a defined target might offer pharmacological advantages over reversibly binding agents — for example, enhanced potency, selectivity and a prolonged duration of action. This is reviewed by Singh and colleagues, who describe how structure-based drug design may be used to optimize the binding and reactivity of such 'covalent drugs', thereby reducing the safety risks that have traditionally discouraged efforts to develop them. Meanwhile, in their Perspective, Neidle and colleagues discuss how stabilizing G-quadruplexes — four-stranded DNA structures that are over-represented in gene promoters — can result in transcriptional repression of various oncogenes, revealing a novel anticancer strategy. Recent progress in the development of small-molecule ligands to target G-quadruplexes is presented. Cancer is among the diseases in which dysregulated nitric oxide (NO) production has been pathologically implicated, and targeting the endogenous NO synthase inhibitor ADMA may represent a therapeutic strategy. In their Review, Leiper and Nandi discuss approaches for manipulating the activity of the enzymes responsible for ADMA metabolism, to control NO production in disorders including cancer, cardiovascular disease, renal disease and sepsis.
