Engineering protein-based therapeutics through structural and chemical design

Protein-based therapeutics have led to new paradigms in disease treatment. Projected to be half of the top ten selling drugs in 2023, proteins have emerged as rivaling and, in some cases, superior alternatives to historically used small molecule-based medicines. This review chronicles both well-established and emerging design strategies that have enabled this paradigm shift by transforming protein-based structures that are often prone to denaturation, degradation, and aggregation in vitro and in vivo into highly effective therapeutics. In particular, we discuss strategies for creating structures with increased affinity and targetability, enhanced in vivo stability and pharmacokinetics, improved cell permeability, and reduced amounts of undesired immunogenicity. Ebrahimi and Samanta review the key advances in the chemical and structural modification of proteins that have enabled their rise as indispensable tools in medicine and outline emerging protein engineering strategies that can potentially unlock structures with improved therapeutic properties.

Automated summary

Protein-based therapeutics have revolutionized disease treatment, with proteins projected to be among the top selling drugs in the near future. This review discusses the design strategies that have transformed protein-based structures into effective therapeutics and highlights emerging protein engineering strategies. Such strategies aim to enhance the stability, targetability, cell permeability, and reduce immunogenicity of proteins, paving the way for improved therapeutic properties.