Volume 22 Issue 1, January 2023

Biogen and Denali’s pivotal trial of a first-in-class LRRK2 kinase inhibitor is a long-awaited test of a target that could provide a path to disease-modifying therapies for Parkinson disease.

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.

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.

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.