Review Articles in 2022

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons. In their Review, Shaw and colleagues provide a comprehensive picture of the various pathological mechanisms involved in this complex disease, and discuss the deep and diverse pipeline under development to tackle these processes. They highlight advances in ALS translational research that might be broadly applicable to other neurodegenerative disorders.

Single-agent therapies targeting specific dysregulated pathways in cancer can be highly effective, but drug resistance frequently develops. Here, Bernards and colleagues discuss the mechanisms underlying resistance to targeted therapies, and assess how these can be suppressed by using tailored combination therapies.

The potential of therapeutically targeting phosphoinositide kinases (PIKs) beyond the class I PI3Ks is increasingly being realized. Here, Burke et al. describe the structure, function, regulation and roles in disease of all clinically relevant PIKs outside of the class I PI3Ks, assessing potent and specific small-molecule inhibitors in development.

The discovery of the monoclonal antibody trastuzumab almost 25 years ago revolutionized treatment and drug development for HER2⁺ breast cancer. Here, Swain et al. review the current standard of care for HER2⁺ breast cancer, describe mechanisms of drug resistance and focus on next-generation platforms and therapies for the treatment of this disease.

Studies of human genetics have been used to identify promising drug targets, and might also inform safety assessment in the drug discovery process. In their Review, Ward and co-authors from industry discuss how genetic studies of rare and complex human diseases can be used to predict potential on- and off-target effects associated with modulating a given target. They also outline suggested best practices for incorporating human genetic data into safety assessments during drug development.

Tumour suppressor gene TP53 is frequently mutated in cancer, and therapeutic strategies to restore the functionality of p53 in tumours have been pursued for decades without success. This Review discusses the promising approaches towards p53-based therapy that have emerged in recent years.

Replication stress is a cause of genome instability in cancer cells. This Review discusses strategies to increase replicative stress by inhibiting the checkpoint kinases that coordinate DNA damage response and cell cycle, as well as combination strategies with other targeted therapies.

The exploitation of cytokines for therapeutic use has been limited by their pleiotropic activity, which has contributed to dose-limiting toxicity and lack of efficacy. Here, Garcia and colleagues discuss how recent insights from structural biology, protein engineering and receptor pharmacology have unveiled strategies to overcome cytokine pleiotropy and enable the design of new and improved cytokine-based therapeutics.

The rational discovery of covalent drugs depends on an expanding toolset of techniques. Here, Daniel Nomura and colleagues highlight covalent drugs that have achieved success over the past decade and discuss the tools and strategies that facilitate their discovery, describing two complementary approaches, namely, ligand-first and electrophile-first strategies.

Peptide and protein drugs have proven successful in the treatment of a wide range of diseases, but their use can be limited by their inherent short-life and need for parenteral administration. Here, Kurtzhals et al. discuss how fatty acid derivatization can be applied to address these issues and optimize the pharmacological properties of peptide and protein drugs, highlighting associated considerations and future directions.

This Review provides an update on the application of small-molecule drugs in immuno-oncology, discussing current development of small molecules designed to stimulate the antitumour immune response directly and indirectly, and the rapidly increasing efforts towards the discovery of small molecules that target T cell checkpoints.

Macrophages can promote tumorigenesis and enhance the antitumour response. This Review discusses the molecular mechanisms underlying the reprogramming of macrophages in the tumour microenvironment and provides an overview of macrophage-targeted therapies for the treatment of cancer.

The potential of therapeutically targeting RNA structures with small molecules is being increasingly recognized. Here, Disney and colleagues review strategies to identify, validate and optimize small-molecule RNA binders. Examples of existing RNA-targeted small molecules, as well as challenges and future directions in the field, are discussed.

Antibody function is dependent on avidity — the accumulated strength of multiple affinity interactions between the antibody, antigen, cell surface receptors and other antibodies. In this Review, Oostindie et al. discuss the role of avidity in eliciting antibody functional responses and review the current engineering strategies for manipulating avidity interactions in antibody-based therapies.

Monoclonal antibodies (mAbs) are appealing as potential therapeutics and prophylactics for viral infections. This Review describes advances in antibody discovery and engineering that have led to the development of mAbs that target viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus and Ebola virus, and also considers the implications for vaccine development.

Multiple sclerosis (MS) is an immune-mediated neurological disorder featuring central nervous system demyelination. Increasing understanding of the complex pathophysiology of this disease has led to considerable expansion of the MS therapeutic toolbox over the past 20 years, but substantial limitations remain. In this Review, Sven Meuth and colleagues highlight promising non-classical targets for MS that could provide fruitful avenues for future therapies.

Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. Here, Mehrotra and Ravichandran discuss the mechanisms of efferocytosis and the role of this physiological process in disease, and assess strategies and agents for therapeutic intervention.

The widespread clinical translation and commercialization of cell-based therapies are hampered by challenges related to cell source, viability, potency, safety and scalability. Here, Veiseh and colleagues overview progress in the development of cell-based therapeutics and discuss how biological engineering approaches — including genome editing, synthetic biology and the use of biomaterials — are beginning to address key challenges in the field.

System-wide methods to monitor protein activity are still underused in drug discovery. This Review discusses the potential of proteomics and chemoproteomics approaches for target identification, validation and identification of safety hazards.

This Review summarizes the basic mechanisms that regulate natural killer cells and the various drugs, cytokines and antibodies that are currently being developed to stimulate natural killer cell responses in cancer treatment.