1. Stereoselective recognition of the Ac-Glu-Tyr-OH dipeptide by pseudopeptidic cages
Enrico Faggi, Cristian Vicent, Santiago V Luis, Ignacio Alfonso Org Biomol Chem. 2015 Dec 28;13(48):11721-31. doi: 10.1039/c5ob01889g. Epub 2015 Oct 20.
Pseudopeptidic molecular cages are appealing receptors since they can display different polar and non-polar interaction sites in a modular framework and a controlled disposition. Inspired by previous host-guest knowledge, two pseudopeptidic molecular cages based on serine and threonine (CySer and CyThr, respectively) were designed and synthesized as hosts for the binding of the four possible stereoisomers of the Ac-Glu-Tyr-OH dipeptide, a target sequence of tyrosine kinases. The careful NMR titration experiments in aqueous acetonitrile allowed the determination of the binding constants and reflected a difference in the stability of the corresponding diastereomeric host-guest complexes. The CySer cage proved to be slightly more efficient than the CyThr counterpart, although both showed similar stereoselectivity trends: LL > DD ≥ LD > DL. This stereoselective binding was retained in the gas phase, as shown by ESI-MS competition experiments using the enantiomer-labelled method (EL), as well as CID experiments. Thus, the MS-determined discriminations follow the same trends observed by NMR, suggesting that the stereoselectivity observed for these systems must be mainly dictated by the polar host-guest interactions. Despite the stereoselective binding of short peptide sequences in competitive media being a challenging issue in supramolecular chemistry, our results demonstrate the power of pseudopeptidic cages in molecular recognition with foreseen implications in chemical biology.
2. The synthesis of neurotensin
R Carraway, S E Leeman J Biol Chem. 1975 Mar 10;250(5):1912-8.
A tridecapeptide having the amino acid sequence, less than Glu-Leu-Tyr-Glu-Asn-Pro-Arg-Arg-Pro-Tyr-Iie-Leu-OH, (The nomenclature and symbols follow the suggestions of the IUPAC-IUB Commission on Biochemical Nomenclature (1972) J. Biol. Chem. 247, 977).) has been synthesized by the Merrifield solid-phase procedure. The synthetic scheme chosen involved synthesis of the peptide in the (Gln) form and cyclization to the less than Glu) form. After purification, the (Gln) peptide was obtained in a 7% yield and the (greater than Glu) peptide was obtained in a 35% yield. The (greater than Glu) was found to be chemically and biologically indistinguishable from the tridecapeptide, neurotensin, recently isolated from bovine hypothalami.
3. Neurotensin: peptide for the next millennium
B M Tyler-McMahon, M Boules, E Richelson Regul Pept. 2000 Sep 25;93(1-3):125-36. doi: 10.1016/s0167-0115(00)00183-x.
Neurotensin is an endogenous tridecapeptide neurotransmitter (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH) that was discovered by Carraway and Leeman in bovine hypothalami in the early 1970s. Since then this peptide has been the subject of a multitude of articles detailing discoveries related to its activity, receptors, localization, synthesis, and interactions with other systems. This review article does not intend to summarize again all the history of this fascinating peptide and its receptors, since this has been done quite well by others. The reader will be directed to these other reviews, where appropriate. Instead, this review attempts to provide a summary of current knowledge about neurotensin, why it is an important peptide to study, and where the field is heading. Special emphasis is placed on the behavioral studies, particularly with reference to agonists, antagonists, and antisense studies, as well as, the interaction of neurotensin with other neurotransmitters.
