Novel strategy to develop stable peptide drugs
Researchers at the École Polytechnique Fédérale de Lausanne (Switzerland) have used cysteine bridges to create complex, stable peptide structures that are able to bind to specific motifs and modulate protein activity.
A team at the École Polytechnique Fédérale de Lausanne (Switzerland), led Professor of Molecular Biology Christian Heinis, have developed a strategy for controlling the structural geometry of short peptide strands by using two or more cysteine bonds. This technique allows for the design of diverse stable peptide structures, which the group has screened to identify potential drugs.
Peptides, short chains of amino acids, can bind to proteins to modulate their function. As they are easy to synthesize, and have high binding affinities and often low toxicity, peptides are commonly used therapeutically with naturally produced examples including insulin and oxytocin.
However, the use of peptide drugs comes with significant challenges. In order to achieve effective binding, peptides must be complementary to the charge and shape of their target site and are often required to fold into complex geometries. Due to their size, peptides are also easily broken down by enzymes, such as proteases, rendering them functionless.
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Heinis’s team has been attempting to tackle these challenges by creating simple peptides of 10–15 amino acid chains, which are intra-linked by cysteine bridges, each joining between two cysteine amino acids to fix the short chains in unusual geometries. By generating different structures from available amino acids and changing the location of the cysteine bridges, the group generated libraries of scaffolds with a huge diversity of structural geometries.
The team next screened these structure libraries, identifying a number of high affinity binders to common protein targets. These targets included kallikrein, a plasma protein indicated in hereditary angioedema, and interleukin 17, a cytokine protein implicated in the inflammation pathway in rheumatoid arthritis and psoriasis.
The team found that their identified leads were able to bind efficiently at nanomolar concentrations. The selected peptides that also proved to be stable to enzyme degradation so may be able to more effectively reach targets through topical or oral delivery.
Heinis and his group are now working on expanding their structural library and screening it with further drug targets, as well as preparing identified leads for pre-clinical evaluation.
Kale SS, Villequey C, Kong XD, Zorzi A, Deyle K and Heinis C. Cyclization of peptides with two chemical bridges affords large scaffold diversities. Nat. Chem. (Epub ahead of print) doi: 10.1038/s41557-018-0042-7 (2018); https://actu.epfl.ch/news/double-bridged-peptides-bind-any-disease-target/