Abstract
Using a novel drug discovery technology reported in previous issues of this journal cyclic peptides have been created which are able to down-regulate secretion of inflammatory cytokines, in vitro, by stimulated cells of the macrophage cell line J774. The cytokines in question, TNF-alpha and IL-6, are strongly implicated in etiology of diseases such as rheumatoid arthritis. Studies are reported here using the CAIA animal model for rheumatoid arthritis, which show that the peptides identified are indeed able to impact on inflammation of joints, induced in vivo. The results suggest that these peptides are effective at a dose which could be viable in man, and at which no adverse side effects are evident in the short term.
Highlights
Drug molecules can have many striking effects when tested in vitro in cell culture models, but, for many reasons, there is no guarantee that these effects will translate into comparable therapeutic activity in an in vivo experimental model
Culture conditions reflected the in vivo situation only approximately, peptide concentrations being maintained at a high concentration for eighteen hours, the stimulation of cells taking place two hours after introduction of the peptide, and the culture medium containing a relatively low concentration of serum components (~10% foetal bovine serum)
An important conclusion is that, despite their small size, the internally-constrained cyclic octaand deca-peptides designed according to the principles described here are capable of eliciting biological responses in vivo with significant therapeutic implications, and that this capability is in major part due to the high degree of rigidity built in to the peptides, and the planar topographical distribution of the side-chain residues
Summary
Drug molecules can have many striking effects when tested in vitro in cell culture models, but, for many reasons, there is no guarantee that these effects will translate into comparable therapeutic activity in an in vivo experimental model. A very important part of the development process for any potential therapeutic agent is a clear transfer from in vitro to in vivo models, and in the case of the peptides described here, this transition was conducted in three stages. The first stage was to try and create a situation in a rodent as close as possible to the ‘test-tube’ culture conditions already employed. In this first experiment, the same stimulus was employed (lipopolysaccharide—LPS), and the same outcome monitored (TNF secretion, and inhibition thereof). As part of the discovery process, micelles were first created with prototype epitopes on their surfaces, before progressing to micelle-free cyclic peptides
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