Due to the short half-life and quick metabolism of peptide medications, pharmaceutical chemists have experimented with a wide range of strategies for increasing the peptide’s metabolic stability. Pharma Grade Explain more –
Switch out L-type for D-type or synthetic amino acids
Although the natural L-type amino acid serves as the primary recognition site of protease in vivo, substituting a D-type amino acid for the L-type at the metabolic site can reduce the peptide’s affinity for protease without affecting its physiological function.
To put it simply, triptorelin is a synthetic version of GnRH. Three artificial amino acid residues are inserted into positions 1, 6, and 10 of the native GnRH. Findings indicate that following intravenous injection, its half-life is increased to 2.8 hours, from 5 minutes for natural GnRH. It is mostly eliminated through the kidneys and liver. https://pharmagrade.store/sarms-and-tanning/
Triptorelin’s chemical make-up
Triptorelin’s molecular structure is seen in Fig. 1. (The 6 and 10 in red are unnatural amino acid residues)
Changes made to either the N or C termini
Both the N- and C-terminal amino acid residues of linear peptides are vulnerable to hydrolysis by exopeptidases; therefore, modifying the terminal residues through methylation or N-acetylation can protect the peptide medicines from breakdown in the metabolic process.
Two to five minutes is the half-life of glucose-dependent insulinotropic polypeptide (GIP). Acetylation of Tyr1 (N-AcGIP) in GIP by Mabilleau et al. created an enzyme-stable GIP analogue with a half-life higher than 24 hours in vivo.
Circularity or bicyclic motion
The linear peptide is easily deformed and binds to the protease’s catalytic site due to its unstable shape. The peptide structure can be stabilised by using the cyclic approach, which also lowers the binding constant (Ka) and affinity of the peptide to protease. At the same time, peptide stability can be greatly improved by cyclization, which protects amino acid residues at both ends or metabolic sites. About 66 percent of all peptide medicines are cyclic peptide compounds. Take, as an illustration:
Natural antibiotics like cyclosporine and daptomycin are cyclic peptides. After 2 hours of incubation, cyclosporine is still more than 90% intact from gastrointestinal peptidases. For example, Sandimmune® is a lipid-based preparation, while Neoral® is a microemulsion with increased bioavailability. After ingested, Neoral® has a half-life anywhere between 5 and 18 hours.
High water solubility and mobility, low toxicity and immunogenicity, and simple clearance from the body are just some of the drug-related benefits of PEG. When a medicine is changed with PEG, similar qualities are obtained; the transfer of these properties is positively connected with the molecular weight of PEG. The molecular weight and steric hindrance of a peptide can be greatly increased with PEG modification at the carboxyl terminus. Site-specific pegylation of GLP-1, as demonstrated by Lee et al., greatly extends the peptide’s plasma half-life in rats by a factor of 16.
Reducing glomerular filtration rate and renal clearance are other key goals of PEG modification with high molecular weight. Together, they significantly increase the elimination half-life in vivo.
After albumin has been taken up by a cell, it forms a strong interaction with FcRn at pH 6 in endosomes, shielding it from destruction in the lysosome. After being secreted from the cell, the mixture enters the extracellular environment, where it neutralises to a pH of 7.4. Modifications to the peptide’s fatty chain were made in response to this pathway, allowing the peptide to bind albumin. This technique was used to greatly lengthen the half-lives of both liraglutide and exemestane. Covalent binding of peptide and albumin, recombinant expression, etc., are further study approaches.
Combining enzyme inhibitors with liposomes or other sustained-release preparations to protect free peptides is another way to increase a drug’s half-life in vivo.
It is crucial for the success of peptide clinical development that researchers learn more about the metabolic stability of peptides and find metabolic pathways and locations early on so that they can make structural alterations to improve therapeutic stability. These days, there are a plethora of long-acting peptide medications and slow-release delivery formulations available on the market. Peptides will have the potential to cure a wider range of ailments as scientific understanding expands and new molecular kinds become available, such as multifunctional peptides, peptide-coupled medicines, and others.