Multi-receptor agonist peptides are one of the fastest-growing areas in metabolic disease. Molecules such as amycretin, a dual GLP-1 and amylin receptor agonist, combine two full-length bioactive sequences, a non-natural N-terminal residue, and a C-terminal primary amide in a single construct that can exceed sixty residues. That length is past what standard SPPS and LPPS handle well. Coupling efficiency, deletion sequences, and solvent use get worse with every extra residue.

Sinopep-Allsino produces the core amino acid sequence by microbial fermentation and limits chemical synthesis to what fermentation cannot deliver: a non-natural N-terminus, a C-terminal primary amide, and site-selective fatty-acid installation. This hybrid approach is meant to give long, multi-domain peptides higher yield and purity, with a smaller environmental footprint than a fully chemical route.

The challenge: beyond traditional SPPS and LPPS

Amycretin is 68 residues. It joins a GLP-1 receptor agonist sequence and an amylin receptor agonist sequence with a short linker, then adds a fatty-acid sidechain on an internal lysine for half-life extension, the same albumin-binding idea used in liraglutide and semaglutide. Two features sit outside microbial expression. Aib at position 2 helps block DPP-4 cleavage but is not in the genetic code, and the C-terminal primary amide is a modification most industrial hosts do not install.

Those constraints stack on a long chain. Even at 99.5% step efficiency, a 68-mer accumulates truncations. Solvent and resin use scale with length, and closely related deletion sequences become harder to separate.

Figure 1. Domain architecture of amycretin: GLP-1 and amylin sequences, linker, and half-life sidechain. Full labeled figure in the paper.

A hybrid platform

Instead of building all 68 residues chemically, the platform expresses residues 3 through the native C-terminus as one recombinant fragment. That fragment omits only the His-Aib N-terminus and carries a cysteine handle in place of the native amide. It is produced as a thioredoxin fusion, then cleaved and purified so the long GLP-1/amylin sequence comes from the host’s own translation machinery rather than from 68 stepwise couplings.

Figure 2. Recombinant fragment production and tag cleavage. Process schematic in the paper.

Completing the molecule

Three chemical steps finish the drug substance after the recombinant fragment is in hand:

• N-terminal capping — install the His-Aib dipeptide
• Photochemical C-terminal amidation — convert the cysteine handle to the native primary amide in flow
• Site-selective lipidation — attach the C18 diacid–γGlu–AEEA–AEEA chain on the remaining lysine

The full white paper includes the complete figures, the photochemical amidation discussion (including reported yield on an analogous long co-agonist), and Sinopep-Allsino’s stated yield, purity, and scale advantages for this hybrid route. To download the full white paper, click the button below.