Automated solid-phase peptide synthesis to obtain therapeutic peptides

Abstract

SummaryThe great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS) offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

High metabolic in vivo stability and bioavailability of a palmitoylated ghrelin receptor ligand assessed by mass spectrometry

“…To overcome these disadvantages, PEGylation, lipidation or the introduction of D-amino acids can be applied. 24,25 Lipidation of a compound leads to more hydrophobic analogs that can build micelles or bind to plasma proteins, for example, serum albumin. 26 Additionally, modification with lipids can improve pharmacokinetics and enhance membrane binding.…”

Identification of snake bradykinin-potentiating peptides (BPPs)-simile sequences in rat brain – Potential BPP-like precursor protein?

“…Peptides synthesis was performed on an automated PSSM-8 peptide synthesizer (Shimadzu Corp.), by a stepwise solid-phase method, using N-9-fluorenylmethoxycarbonyl (Fmoc) chemistry [40]. Cleavage of the peptide from the resin was achieved by treatment with a mixture of TFA/1,2-ethanedithiol/ethyl methyl sulfide for 2 h at room temperature.…”

CHAPTER 6. Amino Acids and Peptides in Ball Milling

“…One of the major advantages is the possibility to fully automate such a process. 6,7 Nevertheless, while being extremely practical and efficient, these methods make use of large amounts of solvent. To produce 1 kg of peptide it is thought that 5000 kg of solvent are needed.…”