Cytokines are secreted or membrane-presented molecules that mediate broad cellular functions, including development, differentiation, growth and survival. Accordingly, the regulation of cytokine activity is extraordinarily important both physiologically and pathologically. Cytokine and/or cytokine receptor engineering is being widely investigated to safely and effectively modulate cytokine activity for therapeutic benefit. IL-2 in particular has been extensively engineered, to create IL-2 variants that differentially exhibit activities on regulatory T cells to potentially treat autoimmune disease versus effector T cells to augment antitumour effects. Additionally, engineering approaches are being applied to many other cytokines such as IL-10, interferons and IL-1 family cytokines, given their immunosuppressive and/or antiviral and anticancer effects. In modulating the actions of cytokines, the strategies used have been broad, including altering affinities of cytokines for their receptors, prolonging cytokine half-lives in vivo and fine-tuning cytokine actions. The field is rapidly expanding, with extensive efforts to create improved therapeutics for a range of diseases.

Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.

Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.