Optimised Peptides
Constructive.bio optimises existing peptide therapeutics and develops novel peptides through simultaneous incorporation of up to 3 different non-canonical amino acids, addressing stability, selectivity, and pharmacokinetics in a single molecule. Our fermentation platform enables rapid structure-activity exploration across hundreds of multi-ncAA variants — a combinatorial capability that chemical synthesis cannot match economically.
The Problem
Peptide therapeutics suffer from rapid proteolytic degradation (plasma half-life often <30 minutes), poor membrane permeability, and limited target selectivity between related receptors. Conventional optimisation uses single modifications — a D-amino acid here, a PEG chain there — applied sequentially because each change requires a new SPPS synthesis. The combinatorial space of multi-site modifications remains largely unexplored because the cost and time of chemical synthesis scale linearly with the number of variants.
Our Approach
Constructive.bio’s genetic code expansion platform incorporates multiple different ncAAs simultaneously during ribosomal translation. Aib or D-amino acids at protease-labile sites provide degradation resistance. Fluorinated amino acids enhance metabolic stability and modulate receptor selectivity. Lipidated ncAAs tune pharmacokinetics for extended half-life. Because all modifications are encoded genetically, variant libraries exploring combinations across 2–3 modification sites can be produced via fermentation in parallel, at a fraction of the per-variant cost of SPPS.
Key Capabilities
Up to 3 different ncAAs per peptide, with multiple instances of each, in a single fermentation
Combinatorial multi-site SAR: hundreds of variants produced in parallel via fermentation
Per-variant cost a fraction of SPPS for multi-ncAA peptides
Simultaneous optimisation of stability, selectivity, and PK in one molecule