'Dual bridge' amino acid developed
1 Sep 2014
Artificial amino acids can impact the 3D structure of bioactive peptides and enhance their potency, according to new research.
Researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland have taken on the challenge of developing drugs that are highly effective against a target, but with minimal toxicity and side-effects to the patient.
According to scientists, such properties are directly related to the 3D structure of the drug molecule.
The EPFL team, therefore, has have developed a synthetic amino acid that can impact the 3D structure of bioactive peptides and enhance their potency.
“Usually when you tamper with a natural molecule, you end up making it worse
EPFL researcher Christian Heinis
Until recently, the vast majority of amino acid-based drugs occurred in nature.
However, the mounting burden of diseases means that newer and more effective medications must be developed; for example, bacterial resistance is growing globally, pushing our need for novel antibiotics.
One way to address this need is the cutting-edge field of directed evolution, which mimics natural selection in the lab to evolve and develop new peptides and proteins.
The EPFL team has developed a synthetic amino acid whose unique structure can considerably increase the effectiveness of therapeutic peptides and proteins. The synthetic amino acid has a very similar structure to a natural amino acid called cysteine, the researchers said.
One crucial difference to the five cysteine-like amino acids the EPFL developed, however: each one could form two bridges instead of just one. The team achieved this by replacing cysteine’s single sulphur group with a branch containing two sulphur groups.
“Usually when you tamper with a natural molecule, you end up making it worse. In this case, we found the exact opposite, which is very exciting,” said study leader Christian Heinis.
The team focuses on therapeutics, where they have a strong background in developing “bicyclic” peptides - peptides that contain two rings in their structure.
Bicyclic peptides have grown into a new class of therapeutic peptides that can be used on disease target that conventional small molecules or large antibodies cannot reach, the researchers said.
Heinis’ group has generated bicyclic peptides against a range of disease targets using directed evolution.
“In our work with bicyclic peptides, we learned that wide structural diversity in peptide libraries is key for achieving good binding. With this new amino acid, it is possible to produce highly diverse peptide structures,” Heinis said.
The EPFL team will now use the new amino acid in directed evolution experiments. Its structural features and its ability to efficiently make cyclic peptides makes the synthetic amino acid a promising candidate for developing new, effective polycyclic peptides for targeted therapy.
