A new ligand extends the half-life of peptide drugs from minutes to days

Peptides are biological molecules, made up of short sequences of amino acids. Because they are easy to synthesize, show low toxicity and high efficiency, peptides such as insulin and other hormones can be used as drugs. But peptides are quickly cleared by the kidneys, which means that we can only use peptide drugs that act within minutes. This problem can be overcome by connecting peptides to ligands that bind blood-serum proteins such as albumin, allowing the peptide to linger in the bloodstream longer. EPFL scientists have now developed such a ligand, which is easy to synthesize and has a high affinity for human albumin. Published in Nature Communications, the new ligand could potentially extend the half-life of peptides from minutes to several days.

Peptides combine a number of attractive features for drugs: low toxicity and immune reactions, high affinity and efficacy for their targets, and accessible chemical synthesis. The only problem is "renal clearance": peptides are generally cleared by the kidneys within a few minutes of entering the patient's blood. For example, one of the most common peptides, insulin, has a bloodstream half-life of only 4-6 minutes. Another hormone, oxytocin -- given intravenously to induce or accelerate labor -- has a half-life of 10-15 minutes.

Such short timeframes imposed by renal clearance severely limit the therapeutic potential of these potentially ideal drugs. One promising way to increase the half-life of peptides is to "piggy-back" them onto blood-serum proteins, such as albumin, which is the most abundant protein in the blood serum and has a half-life of nineteen days. This however, requires an intermediate ligand molecule that can be attached to the peptide during synthesis, and also have a high affinity and selectivity for human albumin.

The lab of Christian Heinis at EPFL has now developed such a ligand, which has a high affinity for human albumin and -- more importantly -- is easy to synthesize and attach to a peptide. The ligand is made by fusing a fatty acid with another peptide. The resulting molecule is referred to as a "chimera" and combines the best of two worlds from the field of albumin ligands.

Previous efforts built ligands based on either fatty acids or peptides, and have tried them on insulin. But whereas fatty acids somewhat extended the half-life of insulin, they generally didn't bind albumin very strongly. On the other hand, peptide-based ligands bind albumin well, but showed low solubility, meaning it didn't distribute insulin in the blood very well.

The new ligand literarily brings together the advantages of both fatty acids and peptides. The researchers searched for an amino acid sequence that would complement the fatty acid's weak binding of albumin. Using an elegant "iterative" synthesis and screening method they discovered a peptide sequence that increases the binding of the fatty acid twenty-seven times. The final chimera ligand binds human albumin with high affinity (Kd = 39 nM), is highly soluble, and can be appended to peptide drugs using standard synthesizing techniques.

The researchers demonstrated in vivo that the ligand prolongs the half-life of several bioactive peptides more than 25-fold. They then appended the ligand to an actual peptide developed to treat pathogenic thrombosis, which has a notoriously impractical short half-life. The ligand was shown to extend the effectiveness of the peptide by several hours, inhibiting the disease in rabbits.

"We expect that the tag presented in our work will interest a larger research and business audience because it is applicable to virtually any peptide moiety, including small proteins," says Heinis. "The ligand can be appended to any peptide during solid-phase peptide synthesis on standard synthesizers, making it easily accessible for academic and industry labs."

The innovative technology can potentially also be applied to modulate the pharmacokinetic properties of bicyclic peptides developed by Bicyclic Therapeutics, a startup co-founded by Christian Heinis and Sir Greg Winter (MRC LMB Cambridge, UK) in 2009, and of which EPFL is a shareholder. On June 1 this year, Bicycle Therapeutics received a series B investment of 52 million US dollars. The company's focus is the bicyclic peptide (Bicycle®) product platform, which combines properties of several therapeutic entities in a single modality: exhibiting the affinity and selective pharmacology associated with antibodies; the distribution kinetics of small molecules, allowing rapid tumor penetration; and the "tuneable" pharmacokinetic half-life and renal clearance of peptides.

Alessandro Zorzi, Simon J. Middendorp, Jonas Wilbs, Kaycie Deyle, Christian Heinis.
Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides.
Nature Communications 8, 16092. DOI: 10.1038/ncomms16092.

Most Popular Now

The Merck Accelerator Program 2019

The Merck Accelerator is looking for real partners so that you can work together in shaping the future. With programs in the headquarters in Germany, in China and the Sat...

Pre-clinical success for a universal flu vaccine o…

Researchers from the University of Oxford's Department of Zoology have demonstrated pre-clinical success for a universal flu vaccine in a new paper published in Nature Co...

Imfinzi is the first immunotherapy to demonstrate …

AstraZeneca and MedImmune, its global biologics research and development arm, have presented data on overall survival (OS) in the Phase III PACIFIC trial of Imfinzi durin...

Global survey reveals that physicians need more in…

Results from a new global survey revealed that more than one-third (36%) of the 310 physicians surveyed do not think they have sufficient information required to make inf...

In clinical trials, new antibody therapy controls …

Thanks to improvements in antiretroviral therapy, HIV is now a manageable condition. Yet even the best drugs do not entirely eliminate the virus, which latently lingers i...

Sandoz Healthcare Access Challenge #SandozHACk ret…

Sandoz, the Novartis generics and biosimilars division, today announces the launch of the second Sandoz Healthcare Access Challenge (HACk). The #SandozHACk is a global co...

The Nobel Prize in Physiology or Medicine 2018 was…

Cancer kills millions of people every year and is one of humanity's greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor c...

Novartis licenses three novel anti-infective progr…

Novartis announced today that it has entered into a licensing and equity agreement with Boston Pharmaceuticals for the development of three novel anti-infective drug cand...

Pfizer to award more than $3 million in grants to …

Pfizer Inc. today announced the recipients of the Advancing Science through Pfizer Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards. Four grants tota...

FDA approves first treatment for advanced form of …

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squam...

DNA islands effective as 'anti-bacterial drones'

Genomic "islands" that evolved from viruses can be converted into "drones" that disable Staphylococcus aureus, bacteria that are often resistant to antibiotics and pose a...

FDA awards 12 grants to fund new clinical trials t…

The U.S. Food and Drug Administration today announced that it has awarded 12 new clinical trial research grants totaling more than $18 million over the next four years to...