General lack of structural characterization of chemically synthesized long peptides.

Many peptide chemistry scientists have been reporting extremely interesting work on the basis of chemical peptides for which the only characterization was their purity, mass, and biological activity. It seems slightly overenthusiastic, as many of these structures should be thoroughly characterized first to demonstrate the uniqueness of the structure, as opposed to the uniqueness of the sequence. Among the peptides of identical sequences in the final chemical preparation, what amount of well-folded peptide supports the measured activity? The activity of a peptide preparation cannot prove the purity of the desired peptide. Therefore, greater care should be taken in characterizing peptides, particularly those coming from chemical synthesis. At a time when the pharmaceutical industry is changing its paradigm by moving substantially from small molecules to biologics to better serve patients' needs, it is important to understand the limitations of the descriptions of these products and to start to apply the same "good laboratory practices" to our peptide research. Here, we attempt to delineate how synthetic peptides are described and characterized and what will be needed to describe them in regards to how they are well-folded and homogeneous in their tertiary structure. Older studies were done when the tools were not yet discovered, but more recent publications are still lacking proper descriptions of these peptides. Modern tools of analysis are capable of segregating folded and unfolded peptides, even if the preparation is biologically active.

Non-peptide oxytocin agonists.

A library of compounds targeted to the vasopressin/oxytocin family of receptors was screened for activity at a cloned human oxytocin receptor using a reporter gene assay. Potency and selectivity were optimised to afford compound 39, EC50 = 33 nM. This series of compounds represents the first disclosed, non-peptide, low molecular weight agonists of the hormone oxytocin (OT).

Versatile Acylation of N-Nucleophiles Using a New Polymer-Supported 1-Hydroxybenzotriazole Derivative.

The synthesis of a new polymer-supported coupling reagent derived from 1-hydroxybenzotriazole is described. An aminomethylated polystyrene was functionalized by reaction with 3-nitro-4-chlorobenzenesulfonyl chloride (2) followed by treatement with hydrazine hydrate, to give the polymeric N-benzyl-1-hydroxybenzotriazole-6-sulfonamide (4).The polymeric reagent 4 was shown to be highly efficient for the synthesis of amides. The efficiency of 4 could be attributed to its high acidity, conferred by the sulfonyl moiety. The procedure for amide synthesis involves the formation of an activated ester on the derivatized polymer followed, in a second step, by treatment with an amine to generate the amide in solution. Simple filtration allows the separation of the product from the polymeric reagent which in this case plays the role of leaving group. An optimization study of this two-step procedure was performed. As amides are obtained in solution free of reaction byproducts, this method can be used in an automated procedure to recover them directly into a 96 well plate, ready to be used in high throughput screening assays. Thus 4 was shown to be particularly suitable for the high throughput parallel synthesis of amides libraries.