The Improved Method of Head-to-tail Amide Cyclic Peptide with Glu and Asp2016-05-30
There are variety kinds of cyclic peptides, such as disulfide cyclization, amide cyclization, olefin metathesis cyclization, lactone cyclization and so on. In recent years, more and more cyclic peptides were found that have good biological activity, such as anti-tumor, anti HIV, antibacterial, antimalarial, hypnotic, inhibition of platelet aggregatio, anti-hypertension, inhibition of tyrosinase, inhibition of cyclooxygenase and biological activity of oxidase, Estrogen-Like, immune suppression and etc.
Currently, it is very common to make cyclic peptides by amide bond. Amide cyclization includes head-to-tail cyclization, main-to-side chain cyclization and side-to-side chain cyclization. Today, we want to discuss about the head-to-tail amide cyclization.
The combination of solid phase and liquid phase methods is common used in head-to-tail amid cyclization. But it is complex to operate, taking long reaction time, and it has low reaction concentration (less than 1mmol/L). All those factors make peptides to form dipolymer or polymers easily.
We designed a new method especially for cyclic peptides which contain Asp and Glu. It is much easier to operate, taking less time, and it has higher reaction concentration. The purity of crude peptide is increased obviously.
Now, we are taking Cyclo(RGDfK) for example.
The Conventional Method:
The Improved Method:
The road to the synthesis of “difficult peptides”2016-05-05
The last decade has witnessed a renaissance of peptides as drugs. This progress, together with advances in the structural behavior of peptides, has attracted the interest of the pharmaceutical industry in these molecules as potential APIs. In the past, major peptide-based drugs were inspired by sequences extracted from natural structures of low molecular weight. In contrast, nowadays, the peptides being studied by academic and industrial groups comprise more sophisticated sequences. For instance, they consist of long amino acid chains and show a high tendency to form aggregates. Some researchers have claimed that preparing medium-sized proteins is now feasible with chemical ligation techniques, in contrast to medium-sized peptide syntheses. The complexity associated with the synthesis of certain peptides is exemplified by the so-called “difficult peptides”, a concept introduced in the 80's. This refers to sequences that show inter- or intra-molecular β-sheet interactions significant enough to form aggregates during peptide synthesis. These structural associations are stabilized and mediated by non-covalent hydrogen bonds that arise on the backbone of the peptide and—depending on the sequence—are favored. The tendency of peptide chains to aggregate is translated into a list of common behavioral features attributed to “difficult peptides” which hinder their synthesis. In this regard, this manuscript summarizes the strategies used to overcome the inherent difficulties associated with the synthesis of known “difficult peptides”. Here we evaluate several external factors, as well as methods to incorporate chemical modifications into sequences, in order to describe the strategies that are effective for the synthesis of “difficult peptides”. These approaches have been classified and ordered to provide an extensive guide for achieving the synthesis of peptides with the aforementioned features.
Hydrocarbon-stapled peptides: principles, practice, and progress
Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent the lion’s share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biological contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chemical interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such solution, conferring α-helical structure, protease resistance, cellular penetrance, and biological activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.