Peptides are ideal drug molecules because of their high affinity, high selectivity, low toxicity and easy synthesis. Unfortunately, peptides have a very short half-life in the body, in part because of enzyme degradation, but mainly because of their small size, which means they can be filtered out of the blood by the kidneys, usually within minutes. For example, once the peptide drug insulin reaches the blood, its half-life is only 4-6 minutes, and the half-life of intravenous oxytocin is only 10-15 minutes.

The rapid renal clearance rate means that most of the approved peptide drugs are designed to work very fast, and the diseases that need to have extended half-life drug treatment cannot be well treated with peptide drugs.

One potential way to extend the circulating half-life of peptides in vivo is to anchor peptides to serum proteins with longer life, such as albumin, by using a ligand. Albumin is the most abundant serum protein with a half-life of 19 days. Ideally, ligands should be easily synthesized and attached to polypeptides with high affinity to albumin. Insulin (insulin)

Detemir, insulin

Degludec and liraglutide are the three most common polypeptide drugs. Their structures contain fatty acids that can bind to albumin. They have been used in the clinical treatment of diabetes.In an in vivo evaluation test, the new ligand extended the half-life of a peptide factor XIIa inhibitor from about 15 minutes to 5.6 hours, and maintained anticoagulant activity in rabbits for up to 8 hours. #FormatImgID_0#

[a bicyclic peptide (white) binds to serum albumin (red) via a newly developed ligand (green))

It is encouraging to note that since the affinity of the tag to rabbit and rat serum albumin is weaker than that of human serum albumin, the half-life of the peptide drug labeled with this chimeric ligand will be longer in human body. In this paper, the researchers said that this high affinity albumin ligand is expected to extend the half-life of peptide drugs in the human body to several days, which will greatly expand the application of peptides as therapeutic drugs, from the short-term preparations that are currently on the market mainly used as receptor agonists to the long-term peptide drugs that need to solve the long-term effects.

Heinis, a professor of EPFL, said the team's work is expected to attract more researchers and pharmaceutical companies. Because the ligands developed by the team are suitable for almost any polypeptide (including small molecule protein) and can be added to any polypeptide in the solid-phase peptide synthesis process of the standard synthesizer, they can be easily used in academic and industrial laboratories.

Professor heinis said that the team is currently using the therapeutic peptide labeled with this ligand to carry out animal research. In the article, however, the EPFL team did not disclose specific therapeutic peptides or target molecules.

There have been previous attempts to develop ligands based on fatty acids or peptides. However, insulin tests showed that although fatty acid ligands were found to extend the half-life of insulin, they did not bind to albumin well. On the contrary, peptide based ligands bind well with albumin, but show poor solubility, which affects the distribution of insulin.

Researchers from the Department of basic sciences and the Institute of chemical science and engineering of the Swiss Federal Institute of Technology (EPFL) have conceived a ligand design that combines the advantages of peptides and fatty acids by coupling fatty acids to short peptides via amino acid side chains. Ideally, fatty acids can bind to albumin alone, and the affinity is in the range of micromol, while the polypeptide part can enhance this affinity by forming additional contact with albumin.

An article published in nature communications is named "acylated heptapeptide bonds album"

with High Affinity and Application as Tag Furnishes Long-Acting

In the article of peptides, EPFL researchers describe an iterative method for ligand development, which is based on multiple rounds of peptide modification and screening. In this way, the researchers obtained a peptide sequence that can increase the binding power of fatty acids by 27 times. The resulting highly soluble chimeric ligand or tag has a very high affinity for human serum albumin (Kd = 39nm), and can be added to peptide drug molecules by standard synthesis technology. In animal models, this new ligand has been shown to extend the half-life of bioactive peptides by 25 times to 7 hours.In addition, the ligand can also be used to effectively modify existing therapeutic peptides, which is also a very attractive application of the tag, and the team expects it to be used for this purpose.

Professor heinis is a start-up biopharmaceutical company based in Cambridge, UK

The co-founder of therapeutics, founded in 2009, has developed a bicyclic peptide treatment platform called bicyle (click: bicyle platform for details), in which EPFL holds a stake. EPFL points out that the new ligands can also be used to improve the dynamic properties of the bicyclic peptide platform of the company.

In June, cycle raised 40 million pounds (US $52 million) in series B financing to promote multiple pipeline projects to clinical trials, including bt1718, a candidate drug for the lead anticancer bicyclic drug conjugate (BDC), which is expected to launch human clinical trials this year. Bt1718 targets membrane matrix metalloproteinase-1 (MT1-MMP), which is expressed in a wide range of solid tumors, including triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).

In December last year, cycle signed a $1 billion cooperation agreement with AstraZeneca, a British pharmaceutical giant, to discover and develop candidate drugs for use in the treatment of respiratory, cardiovascular and metabolic diseases. (compiled by Sina pharmaceutical / newborn)

Bt1718 structure diagram: formatimgid 1#

Article reference:

1、Peptide Half-Life Dramatically Increased Using Novel Approach

2、Acylated Heptapeptide Binds Albumin with High Affinity and Application as

Tag Furnishes Long-Acting Peptides

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