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.

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.

Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding.

No abstract

Data from 93 patients, divided into three equal groups, were used to compare the efficacy of three different doses of insulin - 75iu, 150iu and 300iu - administered twice daily in enteric-coated capsules containing Diabetology’s Axcess™ oral delivery formulation. The study was conducted in 16 centres in India, and comprised a population diagnosed with diabetes for less than two years, with an average BMI of 25.7 kg/m2 and a mean HbA1c of 8.14%. There were no concomitant medications employed other than metformin, whose dose was fixed throughout the study. The study met its primary endpoint of fall in HbA1c ≥0.5 with a high level of significance, and falls in fasting plasma glucose, postprandial glucose, triglycerides and LDL cholesterol were also noted. There was no weight gain in any of the groups over the three-month period. The group demonstrating the highest level of efficacy was the 150iu twice daily group, which was the original anticipated target dose, based on previous studies. The data support progression of Diabetology’s oral insulin programme towards conduct of large-scale phase 3 studies. Disclosure R. R. C. New: Employee; Self; Diabetology Ltd. M. Bogus: None. G. N. Travers: Stock/Shareholder; Self; Axcess Ltd, Diabetology Ltd, Proxima Concepts Ltd, Stock/Shareholder; Spouse/Partner; Axcess Limited, Proxima Concepts Ltd. G. S. Namjoshi: None.