Oral Peptides
Constructive.bio develops orally bioavailable peptides by incorporating up to 3 ncAAs that confer protease resistance, enhanced membrane permeability, and metabolic stability — addressing the three barriers that have historically confined peptide therapeutics to injectable administration. Our fermentation platform produces these modified peptides at scale, bypassing the cost and complexity of chemical synthesis.
The Problem
Peptide therapeutics are almost universally injectable because the GI tract rapidly degrades them. Gastric and pancreatic proteases cleave peptide bonds within minutes, while poor membrane permeability prevents absorption of intact peptide. Oral semaglutide (Rybelsus) achieves only ~1% bioavailability using a permeation enhancer (SNAC), requiring 7mg oral doses to match 1mg injected — a brute-force approach that limits the therapeutic window.
Our Approach
Constructive.bio incorporates ncAAs that directly address each barrier to oral delivery. N-methylated amino acids and D-amino acids at protease-susceptible positions provide resistance to GI degradation without altering target binding. Lipophilic ncAAs increase passive membrane permeability. Backbone modifications using β-amino acids reduce first-pass hepatic metabolism. These modifications are incorporated biosynthetically during fermentation, enabling structure-activity relationship exploration across hundreds of variants without the per-variant cost of chemical synthesis.
Key Capabilities
Up to 3 different ncAAs per peptide targeting protease resistance, permeability, and metabolic stability
N-methylation and D-amino acid substitution at identified protease cleavage sites
Lipophilic ncAA incorporation for enhanced passive membrane permeability
Rapid SAR exploration: hundreds of variants via fermentation, not per-variant chemical synthesis