Natural, Synthetic and Modified Peptides

Origin, method and design are different questions

Three separate questions are often blurred together:

1. Where does the sequence come from? A natural source, or a design.
2. How is it made? Isolated from tissue, built chemically, or produced by living cells.
3. Has it been changed? The natural sequence or an altered version.

A peptide can be "natural" in sequence yet made in a laboratory, or designed with unnatural parts. The FDA draft guidance says peptides can be isolated from animal tissue, produced synthetically, or produced through recombinant expression. [1]

Natural peptides

Natural peptides are chains of amino acids joined by amide bonds, but they lack the stability that folded structure gives larger proteins, and enzymes can break them down. [2] Many bioactive peptides come from bacteria, fungi, plants and animals. [2] Ziconotide, an approved pain medicine, is derived from the neurotoxic peptide of a cone snail, Conus magus. [2]

Synthetic peptides

Chemical synthesis builds a peptide in the laboratory instead of extracting it. A review describes making peptides of fewer than 50 residues with a standard laboratory method (solid-phase synthesis) as relatively routine, while chemical synthesis of longer chains is still challenging at large scale. [2] In cosmetics, process methods now allow nearly unlimited sequences to be made. [3] Most cosmetic peptides are obtained by chemical synthesis or by partial digestion of animal proteins. [3]

Liraglutide, a diabetes medicine, is described as a chemically synthesized analogue of human GLP-1. [2]

Recombinant peptides

Recombinant means living cells, such as bacteria, are engineered to make the peptide. Teduglutide is described as an analogue of glucagon-like peptide 2 made using a modified strain of Escherichia coli. [2] Semi-synthesis combines both approaches by linking synthetic peptides to peptides expressed using recombinant DNA. [2]

Modified peptides

Because natural peptides are unstable, developers often change them to improve absorption, half-life and selectivity. [1] Reported modification strategies include:

• Replacing L-amino acids with D-amino acids, which improves stability against enzymes. [4]
• Adding unnatural amino acids, methylated or beta-amino acids. [2]
• Cyclization, pseudo-peptide bonds and PEGylation (attaching a polyethylene glycol chain). [1]
• Lipidation, attaching a fatty acid, as in liraglutide, semaglutide and tirzepatide, which are all derived from GLP-1. [4]

The FDA notes that peptide drug products can show a distinct mix of characteristics of both small and large molecules. [1] More in lipidation, PEGylation and cyclization.

Why this matters when reading about a product

• A modified analogue is not the natural peptide. Findings about one do not transfer automatically to the other. For example, the FDA lists GHRP-2 as containing an unnatural amino acid, which adds to the complexity of characterizing it. [5]
• Manufacturing method affects impurities. Peptide-related impurities and aggregation are concerns the FDA cites for certain compounded peptides. [5]
• "Natural" or "synthetic" does not decide safety. Safety depends on the specific molecule, purity, formulation, route and person. See natural vs synthetic compounds.

Where the main product categories stand

For the cosmetic category, U.S. cosmetics other than color additives do not need FDA approval before sale. [6] Read more at what are cosmetic peptides.