Unlocking the Potential of Peptide-based Drugs

New computational methods enable custom peptide design for drug discovery.

The Science

Peptides are naturally occurring molecules with excellent pharmaceutical properties, but their therapeutic use has been limited by the relatively small number of natural peptide structures. Powerful new computational methods now enable scientists to design a virtually unlimited variety of hyperstable peptide structures not found in nature, opening a new frontier in drug discovery.

The Impact

The design of custom peptides that fold into previously inaccessible regions provides the foundation for development of a new generation of peptide-based drugs with enhanced pharmacological properties. These new hyperstable constrained peptides promise to be safer, cheaper, and more effective than conventional therapeutics.


Most drugs currently approved for humans are either large proteins or small molecules. Between these two size categories are peptides, molecules with excellent pharmaceutical properties because they combine the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. However, naturally occurring peptide structures are limited in variety, underscoring the need for novel, powerful computational approaches to design a wide range of peptides to fully explore their potential for drug discovery. To address this need, a multi-institutional team of researchers developed new computational methods that predict how a string of amino acid residues folds into a three-dimensional structure, enabling the de novo design of peptides with a broad range of previously inaccessible sizes, shapes, and functions. To show their computational design methods worked, the researchers synthesized a subset of de novo peptides that were 18-47 amino acid residues in length with diverse topologies. The introduction of chemical features constrained their shape and made the new peptides hyperstable, resistant to extreme temperatures and exposure to harsh chemicals. To show these peptides folded as designed, structures for 12 of the synthesized peptides were determined with the assistance of data collected on the high-field nuclear magnetic resonance (NMR) spectrometers at the Department of Energy’s (DOE) Environmental Molecular Sciences Laboratory (EMSL), a DOE Office of Science user facility. The experimentally determined X-ray and NMR structures were nearly identical to those determined from the computational models. The ability to precisely control the size and shape of peptides designed to fit into a specific target binding pocket has potential to unlock a new generation of peptide-based therapeutics to treat a wide variety of diseases. This major advance in peptide-based drug discovery represents a collaborative effort among the University of Washington’s Institute of Protein Design, Seattle Structural Genomics Center for Infectious Diseases, University of Queensland, Pacific Northwest National Laboratory, State University of New York at Buffalo, Fred Hutchinson Cancer Research Center, Novo Nordisk, Cyrus Biotechnology, New York University, Simons Foundation, and Stony Brook University.

Principal Investigator(s)

Garry W. Buchko
Seattle Structural Genomics Center for Infectious Diseases and Pacific Northwest National Laboratory


This work was supported by the Department of Energy (DOE), Office of Science, Offices of Biological and Environmental Research and Advanced Scientific Computing Research, including support of the Environmental Molecular Sciences Laboratory and Argonne Leadership Computing Facility, both DOE Office of Science user facilities, as well as the Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program; University of Washington; Rosetta@Home; National Institutes of Health; Three Dreamers and Washington Research Foundation; Howard Hughes Medical Institute; The Australian Research Council; Northeast Structural Genomics Consortium; National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases; and   Department of Health and Human Services.


Bhardwaj, G., et al. 2016. “Accurate De Novo Design of Hyperstable Constrained Peptides,” Nature 538, 329-335. DOI: 10.1038/nature19791.