synthetic amino acid

Synthetic amino acid enables safe, new biotechnology solutions to global problems .

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Scientists have devised a way to ensure genetically modified organisms can be safely confined in the environment, overcoming a major obstacle to widespread use of GMOs in agriculture, energy production, waste management, and medicine.

Bacteria (stock illustration).

Scientists from Yale have devised a way to ensure genetically modified organisms (GMOs) can be safely confined in the environment, overcoming a major obstacle to widespread use of GMOs in agriculture, energy production, waste management, and medicine.

The Yale researchers rewrote the DNA of a strain of bacteria so that it requires the presence of a special synthetic amino acid that does not exist in nature to activate genes essential for growth. Amino acids are the building blocks of proteins, which carry out life’s functions. This new method of bio-containment, reported online on Jan. 21 in the journal Nature, solves a longstanding problem in biotechnology.

“This is a significant improvement over existing biocontainment approaches for genetically modified organisms,” said Farren Isaacs, assistant professor in the Department of Molecular, Cellular, and Developmental Biology and the Systems Biology Institute at West Campus, and senior author of the paper. “This work establishes important safeguards for organisms in agricultural settings, and more broadly, for their use in environmental bioremediation and even in medical therapies.”

Isaacs, Jesse Rinehart, Alexis Rovner, and fellow synthetic biologists at Yale call these new bacteria genomically recoded organisms (GROs) because they have a new genetic code devised by the team of researchers. The new code allowed the team to link growth of the bacteria to synthetic amino acids not found in nature, establishing an important safeguard that limits the spread and survival of organisms in natural environments.

In a second study, Isaacs, Ryan Gallagher, and Jaymin Patel at Yale devised a strategy to layer multiple safeguards that also limit growth of GMOs to environments that contain a different set of synthetic molecules. Published Jan. 21 in the journalNucleic Acids Research, this study describes a complementary set of distinct and portable safeguards capable of securing a wide range of organisms.

These safe GMOs will improve efficiency of such engineered organisms, which are now being used in closed systems, such as the production of pharmaceuticals, fuels, and new chemicals. Concerns about use of GMOs in open environments, however, has limited their adoption in other areas.

The authors also say that the new code paired with artificial amino acids will allow scientists to create safer GMOs for use in open systems, which include improved food production, designer probiotics to combat a host of diseases, and specialized microorganisms that clean up oil spills and landfills.

“As synthetic biology leads to the emergence of more sophisticated GMOs to address these grand challenges, we must assume a proactive role in establishing safe and efficacious solutions for biotechnology, similar to those who worked to secure the Internet in the 1990s.” Isaacs said.

Story Source:

The above story is based on materials provided by Yale University. The original article was written by Bill Hathaway. Note: Materials may be edited for content and length.

Journal Reference:

  1. Alexis J. Rovner, Adrian D. Haimovich, Spencer R. Katz, Zhe Li, Michael W. Grome, Brandon M. Gassaway, Miriam Amiram, Jaymin R. Patel, Ryan R. Gallagher, Jesse Rinehart, Farren J. Isaacs. Recoded organisms engineered to depend on synthetic amino acids. Nature, 2015; DOI: 10.1038/nature14095

A new synthetic amino acid for an emerging class of drugs

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Swiss scientists have developed a new amino acid that can be used to modify the 3-D structure of therapeutic peptides. Insertion of the amino acid into bioactive peptides enhanced their binding affinity up to 40-fold. Peptides with the new amino acid could potentially become a new class of therapeutics.

One of the greatest challenges in modern medicine is developing drugs that are highly effective against a target, but with minimal toxicity and side-effects to the patient. Such properties are directly related to the 3D of the drug molecule. Ideally, the drug should have a shape that is perfectly complementary to a disease-causing target, so that it binds it with high specificity. Publishing in Nature Chemistry, EPFL scientists have developed a synthetic amino acid that can impact the 3D structure of bioactive and enhance their potency.

Peptides and proteins as drugs

Many of the drugs we use today are essentially naturally-occurring peptides (small) and proteins (large), both of which are made up with the found in all living organisms. Despite the enormous variety of peptides and proteins, there are only twenty natural amino acids, each with a different structure and chemical properties. When strung together in a sequence, amino acids create peptides and proteins with different 3D structures and, consequently, different biological functions.

Until recently, the vast majority of amino acid-based drugs were the kinds occurring in nature: hormones such as insulin, antibiotics such as vancomycin, immunosuppressive drugs such as cyclosporine etc. But 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.

A new amino acid for new peptides

The team of Christian Heinis at EPFL 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. Cysteine is unique among the twenty natural amino acids because it contains a sulfur group. This allows it to form a bridge with another cysteine, and thereby influence the overall 3D structure – and function – of a peptide or protein.

The EPFL researchers initially designed five cysteine-like amino acids, all with one crucial change: each one could form two bridges instead of just one. The team achieved this by replacing cysteine’s single sulfur group with a branch containing two sulfur groups. After synthesizing the five new amino acids, the team integrated them into the structure of two bioactive peptides, one that inhibits an enzyme implicated in cancer, and one blocking a receptor found in neurons.

Testing only a handful of cyclic peptides with the synthetic amino acid, Heinis’ team was able to identify several peptides that showed enhanced activities. The best inhibitor of the neuron receptor was 8-fold improved and the best protease inhibitor had even a 40-fold higher activity.

“This was unexpected”, says Christian Heinis. “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.”

The emerging class of bicyclic peptides

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. 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 aims now to use the new amino acid in directed evolution experiments. Its structural features and its ability to efficiently make makes the synthetic amino acid a promising candidate for developing new, effective polycyclic peptides for targeted therapy.