Scientists hail bottom-up design as the ‘souped-up car’ of proteins
Scientists at the University of Leicester synthesised alkenyl amino acids to create peptide tools for forming biotherapeutics. These unnatural amino acids were selectively produced to be asymmetric (chiral), with right-handedness.
Top-down or bottom-up?
The work represents a new approach to biologics discovery, Andrew Jamieson, leading the discovery team within the university’s Chemistry department, told BioPharma-Reporter.com.
“With biologics, people generally come from the perspective of recombinant expression – producing proteins using E.coli for instance. That’s a ‘top-down’ approach – using organisms to produce proteins.
“Our perspective is ‘bottom up’ – the analogy is: imagine a protein is a car – ‘top-down’ means buying a car and making modifications to produce a souped-up car. Most people will take a protein and modify its sequence to change its function.”
But the team’s method does not draw on synthetic biology, he said.
“We want to build from scratch, from the bottom up, synthesising proteins chemically. To do that you need unnatural amino acids.”
“The advantage of our approach is we can modify the covalent structure of a protein and incorporate any functionality we want, now we can make these building blocks. The limitation of recombinant proteins is they’re limited to the standard twenty amino acids.”
Clinical trials
“The process from design to producing these molecules is extremely quick,” said Jamieson. “The chemistry to then produce the peptides is really straightforward – we use automated synthesisers.”
The team designed synthesised analgaesic molecules for a client within two weeks, he said: “It takes longer to set up the assay than produce the molecules.”
The “conformational- constrained peptides” created with unnatural amino acids bind better to target receptors and possess other sought-after properties, like increased bioavailability and membrane permeability, Jamieson told us.
Conformationally-constrained peptides have made it to clinical trial, with French biotech Aileron completing a Phase I study in May of stapled peptide drug ALRN-5281, a growth hormone-releasing hormone (GHRH) agonist for treating orphan endocrine disorders, including adult growth hormone deficiency and HIV lipodystrophy.
Aileron has a patent on stapled peptides and is working on a pipeline of outlicensed products with various companies.
Source: Robust Asymmetric Synthesis of Unnatural Alkenyl Amino Acids for Conformationally Constrained a-Helix Peptides, Organic & Biomolecular Chemistry, 2014,
