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The aqueous solution conformation of Arg-Lys-Asp-Val-Tyr (TP5), corresponding to positions 32-36 of the thymic hormone thymopoietin has been investigated by proton nuclear magnetic resonance (NMR). This pentapeptide fragment retains the biological activity of the parent protein, viz., induction of selective differentiation of T lymphocytes. All the observed NH and CH resonances of TP5 have been assigned, and the solution conformation of this peptide has been investigated by analysis of chemical shift variations with pH, vicinal NH-C alpha H coupling constant data, and amide hydrogen exchange rates. The latter were measured in H2O by using a combination technique consisting of the transfer of solvent saturation and saturation recovery NMR experiments. The data are compatible with the assumption of a highly motile dynamic equilibrium among different conformations for TP5. A comparison of the amide hydrogen exchange rates of the pentapeptide with that of solvated model compounds shows that Val4-NH is significantly shielded from the solvent. In addition, the chemical shift variations with pH suggest that the guanidino-N epsilon H of arginine is associated with one of the carboxylate groups. These observations provide specific boundary conditions for the construction of molecular models of the conformation(s) of TP5 in aqueous solution.

The insulinotropic hormone glucagon‐like peptide‐1 (7‐36)‐amide (GLP‐1) has potent effects on glucose‐dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP‐1 and two of its long‐acting analogs, exendin‐4 and exendin‐4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP‐1 receptor. We observed that GLP‐1 and exendin‐4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP‐1 receptor antagonist exendin (9‐39). Furthermore, exendin‐4 could promote NGF‐initiated differentiation and may rescue degenerating cells after NGF‐mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3‐(4,5‐cimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP‐1 and exendin‐4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.

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