Chimica Oggi-Chemistry Today
Agro FOOD Industry Hi Tech
Recent peptide research milestones and achieveme
President and C.E.O., Peptides International Inc.

KEYWORDS: Native chemical ligation, cell penetrating peptides, click chemistry, stapled peptides, cyclization of peptides, large scale peptide production.

Peptides have become valuable tools for researchers around the world. As new pharmaceutical targets are investigated, researchers have a need to have special peptide tools to aid in their research. The need for longer and more complex peptides has risen over the past several decades. This short report details some recent milestones in this sector.

Making peptides: balancing dreams and technical feasibility

The dream of many peptide chemists is the ability to synthesize longer and more complex molecules paralleling those which occur in nature. Synthetic techniques have advanced over the past 5 decades allowing for molecules to reach upwards of 100 residues from a linear solid-phase synthesis making mini-proteins accessible. However, one of the most recent achievements which has been advanced in the past 10-20 years is the technique of native chemical ligation pioneered by Dawson and Kent (1). Making use of C-terminal peptide thioesters reacting with another peptide containing a Cys at the N-terminus allows for a chemical ligation reaction which spontaneously rearranges to a native peptide bond at a pH of 7.2. This technique has allowed for chemical synthesis of proteins such as sPLA2  (2) and Kcsa potassium channel (3).
Selective derivatization techniques have been greatly enhanced over the past decade. Click chemistry using copper catalyzed cycloaddition of an azide and an alkyne to form a five membered heterocyclic rings was independently pioneered in the laboratories of Barry Sharpless (4) and Morton Meldal (5). Use of this method has greatly facilitated chemical modification procedures allowing for simple and selective incorporation of expensive reagents such as biotin, fluorescent dyes, chelating moieties, as well as providing access to branched and dendrimeric peptides.
Targeting intracellular non-drugable targets has been advanced with the discovery of peptides which facilitate crossing the cellular membrane. These cell penetrating peptides have the ability to pass through the cell membrane and can be tethered with payload molecules to inhibit internal cellular targets. The first of these protein transduction domains (PTD) discovered was from the HIV TAT protein. The central peptide responsible for cell penetrating properties comes from an Arg-rich sequence residues 47-60 GRKKRRQRRRPPQ (6). Since this initial discovery several other PTDs have been identified such as Antennapedia homeobox domain sequence (7). Using these peptides to deliver small molecules such as doxorubicin, peptides, and siRNAs, several companies have been advancing their CPP conjugates and are currently at various stages of clinical development (8).
More recent research has focused on developing from vast screening approaches using libraries of constrained peptides. These include stapling techniques using amino acids containing olefin sidechains. By exposing the peptide to Grubbs catalyst the result is a ring closing olefin metathesis between the two sidechains (9) This technique has improved the cellular permeability as well as the stability of structural elements in several peptide drugs currently in clinical development (10 )....In order to continue reading this article please register to our website – registration is for free and no fees will be applied afterwards to download contents.

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