Shaping the future of constrained peptides and compact proteins in drug discovery
Sven Ullrich
A *
A
Sven Ullrich is a Feodor Lynen Research Fellow (Humboldt Foundation) at the University of Tokyo, Japan. He holds a degree in pharmacy from Heidelberg University, Germany, and a PhD in chemistry from the Australian National University. During his doctoral studies, he was a visiting student at the University of Alberta, Canada. His research focuses on modified peptides and proteins in genetically encoded libraries for drug discovery. He received the Dr Elizabeth Schram Young Investigator Award at the 27th American Peptide Symposium (2022), was a selected participant at the Global Young Scientists Summit in Singapore (2023) and was recognised as part of the CAS Future Leaders Top 100 initiative (2024). For his graduate work, he was awarded both the John Carver Award (ACT Branch, 2024) and the Cornforth Medal (National, 2024) by the Royal Australian Chemical Institute. |
Abstract
Constrained peptides and compact proteins are potent alternatives to conventional drug modalities in academia and industry. Located in the chemical space between small molecules and classical biologics, these drug formats feature highly modular, conformationally constrained turns and loops that can be accessed through rational design, selection-based screening or computational discovery. The amino acid-derived biopolymers can engage comparatively featureless protein surfaces more effectively than low molecular weight compounds, yet at the same time offer greater potential to reach intracellular targets than larger biologics. This combination allows them to address medicinal chemistry challenges that conventional approaches struggle to solve. In this brief review, selected advances in the discovery and development of such structures are highlighted, especially those where screening of genetically encoded or synthetic libraries played a central role. Several recent examples of rational design and computationally generated peptide and protein scaffolds are also discussed, including those driven by machine learning and artificial intelligence. Across these strategies, all case studies describe the successful identification and refinement of cyclic peptides or compact proteins with antibody-like binding as promising lead structures. As the presented examples cover a wide range of structural topologies and medicinally relevant targets, they reflect the growing importance of cyclic peptides and compact proteins as new molecular modalities for drug discovery and development.
Keywords: antibody-mimetic proteins, artificial intelligence, cyclic peptides, drug design, encoded libraries, macrocyclisation, miniproteins, nanobodies, rational design, therapeutics.
Sven Ullrich is a Feodor Lynen Research Fellow (Humboldt Foundation) at the University of Tokyo, Japan. He holds a degree in pharmacy from Heidelberg University, Germany, and a PhD in chemistry from the Australian National University. During his doctoral studies, he was a visiting student at the University of Alberta, Canada. His research focuses on modified peptides and proteins in genetically encoded libraries for drug discovery. He received the Dr Elizabeth Schram Young Investigator Award at the 27th American Peptide Symposium (2022), was a selected participant at the Global Young Scientists Summit in Singapore (2023) and was recognised as part of the CAS Future Leaders Top 100 initiative (2024). For his graduate work, he was awarded both the John Carver Award (ACT Branch, 2024) and the Cornforth Medal (National, 2024) by the Royal Australian Chemical Institute. |
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