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Advances in the Synthesis of Peptide Therapeutics: Clear Advantages…and Some Barriers

Although peptides were long passed over for drug development, recent technological advances have prompted the pharmaceutical industry to take a closer look at them. The increased sensitivity, resolution and throughput of modern analytical methods have allowed scientists to identify numerous promising new peptides.

In addition, using combinatorial chemistry, we can modify peptides and create artificial variants. Advances in formulations that can mask or rectify peptides’ pharmacodynamic weaknesses have resulted in synthetic peptides being used more and more:

  • as therapeutics
  • as diagnostics
  • to produce antibodies
  • to understand biological processes.

Advances in Peptide Synthesis- Advantages of using secondary structure disruptors

The synthesis of complex peptides has benefited with the introduction of secondary structure disruptors such as pseudoprolines, isoacyl dipeptides, and Dmb (dimethoxybenzyl)-amino acids during the assembly of the peptide chain.

Neuland recently accomplished the liquid phase manufacture of 32kg of a decapeptide, using two pentapeptide key starting materials (KSM). The KSM terminating in a carboxyl group had a pseudoproline which facilitated racemization-free coupling. Without the pseudoproline, about 20% racemization was seen during the 5+5 coupling reaction. Strategic use of pseudoprolines has resulted in the synthesis of peptides containing more than 100 amino acids.

There are three approaches to disrupt secondary structure formation during the peptide-chain assembly.
Pseudoproline dipeptides:

  • are ideally suited to enhancing synthetic efficiency in Fmoc solid phase peptide synthesis
  • increase efficiency, reducing the need for costly repeat syntheses
  • increase purity of crude products
  • simplify HPLC purification
  • boost the yield of crude and purified products
  • allow synthesis to be conducted on a lower scale
  • are especially effective for synthesizing intractable peptides, long peptides/small proteins, and cyclic peptides

Oxazolidine-based dipeptides derived from Ser or Thr are widely used and are commercially available as Fmoc-protected dipeptides. Neuland has introduced about 30-pseudoprolines, available in hundreds of grams to multiple Kgs dipeptides.

Isoacyl dipeptides:

  • enhance the synthetic efficiency in the Fmoc/t-butyl based solid phase strategy. Substituting Xxx-Ser/Thr in a peptide sequence with the corresponding isoacyl dipeptide forms a depsipeptide analog of the native sequence.
  • “de-aggregate” the natural aggregating peptide, aiding purification. The native peptide is regenerated via exposure to slightly basic pH.
  • are versatile building blocks for synthesizing difficult peptides like β-amyloid, making it more soluble and reducing its tendency to form fibrils.

Neuland provides a wide range of Isoacyl dipeptides to the pharma industry.

Fmoc-(Dmb)/Fmoc-(Hmb) amino acids and dipeptides:

  • prevent β-Aspartyl peptide formation
  • aid synthesis of peptides containing multiple glycines

We have a number of Fmoc-(Dmb)(Hmb)amino acid and dipeptides available for use in various therapeutic applications.


While peptides provide clear advantages in therapeutic development, there are some barriers to overcome. One of the major challenges involved with peptide therapeutics is the lack of regulation. Regulatory authorities have yet to define guidelines concerning what level of impurities are allowed to be present in peptide therapeutics.

Another major issue is the fact that most peptides cannot be taken by mouth, due to their rapid inactivation and how poorly they penetrate the intestinal mucosa. As patient compliance is highest when drugs can be taken by mouth, this is a critical barrier holding back the future of peptides. Thus, most peptides must be given by other means of administration, such as through the skin, the nose, into the bloodstream, or even via novel drug delivery systems such as the use of liposomes. In addition to being less convenient for the patient, these methods have also been shown to alter peptide pharmacokinetic profiles, as well as their biological activity.

Peptides are also highly vulnerable to degradation by gastric acid in the stomach and protease in the intestine, and peptide antigenicity can trigger severe immune responses.

Despite these challenges, the future of peptides appears bright, and their presence in the pharmaceutical industry is rapidly expanding.


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