Abstract
Although strong binding interactions between protein receptor and ligand do not require the participation of a large number of amino acids in either site, short peptide chains are generally poor at recreating the types of protein-protein interactions which take place during cell recognition and signalling process, probably because their flexible backbones prevent the side chains from forming sufficiently rigid and stable epitopes, which can take part in binding with the desired strength and specificity. In a recently-reported study, it was shown that a proto-epitope containing F, R and S amino acids has the ability to down-regulate TNF secretion by macrophages. This paper extends these findings, putting those amino acids into a short cyclic peptide scaffold, and determining the optimal configuration required to overcome the problems of conformational instability, and give rise to molecules which have potential as therapeutic agents in human disease, such as rheumatoid arthritis.
Highlights
As a result of conducting the MozaicTM discovery process, it was discovered that when a combination of three amino acids (R, S & F) was presented to J774 cells on the surface of micelles, this preparation was highly effective in inhibiting secretion of TNF from these cells after they had been stimulated with cholera toxin B fragment (CTB) or lipopolysaccharide (LPS)
While reducing TNF secretion could be a very effective therapeutic strategy in rheumatoid arthritis but in many other inflammatory diseases, the labile nature of micelles makes them poor candidates for a therapeutic agent, since they can readily be disassembled in vivo, for example by exchange of lipids with lipoproteins, adsorption onto large proteins, or fusion with cell membranes, followed by dispersion of the component amphiphiles
An approach directed towards constraining the ring was employed, after its formation, in which a pair of extra amino acids was inserted on opposite sides of the ring
Summary
As a result of conducting the MozaicTM discovery process (previously described [1]), it was discovered that when a combination of three amino acids (R, S & F) was presented to J774 cells (a murine macrophage cell line) on the surface of micelles, this preparation was highly effective in inhibiting secretion of TNF from these cells after they had been stimulated with cholera toxin B fragment (CTB) or lipopolysaccharide (LPS). It is envisaged that the amino acids close-packed on the surface of the micelle can come together in many different configurations It was thought most likely that the putative receptor was a protein expressed on the plasma membrane surface, since internalisation of the micelle would result in degradation processes separating the amino acids from each other, so specific interaction could not take place with receptors inside the cell. While reducing TNF secretion could be a very effective therapeutic strategy in rheumatoid arthritis but in many other inflammatory diseases, the labile nature of micelles makes them poor candidates for a therapeutic agent, since they can readily be disassembled in vivo, for example by exchange of lipids with lipoproteins, adsorption onto large proteins, or fusion with cell membranes, followed by dispersion of the component amphiphiles
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
