Although chemists can synthesize virtually any small organic molecule, our ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, modifications are largely restricted to substitutions among the common 20 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and eukaryotic organisms. Over 30 novel amino acids have been genetically encoded in response to unique triplet and quadruplet codons including fluorescent, photoreactive, and redox-active amino acids, glycosylated amino acids, and amino acids with keto, azido, acetylenic, and heavy-atom-containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps entire organisms with new or enhanced properties.

Expanding the genetic code.

Albert Isidro-Llobet, Mercedes Alvarez,* and Fernando Albericio* Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain; CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain; Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain; and Department of Organic Chemistry, University of Barcelona, Marti i Franques 1, 08028 Barcelona, Spain Received April 28, 2008

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Amino Acid-Protecting Groups

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a f...

Neuroendocrine Control of Growth Hormone Secretion

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.

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Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

Hydrogels were the first biomaterials rationally designed for human use. Beginning with the pioneering work of Wichterle and Lim on three-dimensional polymers that swell in water, we review the design, synthesis, properties, and applications of hydrogels. The field of hydrogels has moved forward at a dramatic pace. The development of suitable synthetic methods encompassing traditional chemistry to molecular biology has been used in the design of hydrogels mimicking basic processes of living systems. Stimuli-sensitive hydrogels, hydrogels with controlled degradability, genetically engineered poly(amino acid) polymers reversibly self-assembling in precisely defined three-dimensional structures, and hybrid polymers composed of two distinct classes of molecules are just some examples of these exciting novel biomaterials. The biocompatibility of hydrogels and their applications from implants to nanomaterials are also reviewed. Copyright © 2007 Society of Chemical Industry

Hydrogels as smart biomaterials

(6) H. Hagenmaier and M. Mutter, Tetrahedron Lett., 767-770 (1974). (7) W. Gohring and G. Jung, Justus Liebigs Ann. Chern., 1765-1789 (1975). (8) M. Mutter, R. Uhmann, and E. Bayer, Justus Liebigs Ann. Chern., 901-915 ( 1975). (9) G. Jung, G. Bovermann, W. Gohring, and G. Heusel in "Peptides: Chemistry, Structure and Biology," R. Walter and J. Meienhofer, Ed., Ann Arbor Sci. Publ., Ann Arbor, Mich., 1975, pp 433-437. (10) F A . Tjoeng, W Staines, S. St-Pierre, and R. S. Hodges, Biochirn. Biophys. Acta, 490, 489-496 (1977). (1975). (1 1) L. B. Smillie, PAABS Revista, 5, 183-263 (1976). (12) R. S. Hodges, J. Sodek, L. B. Smillie, and L. Jurasek, ColdSpring Harbor

http://www.sciencemadness.org/talk/files.php?pid=116909&aid=4738

Rapid removal of protecting groups from peptides by catalytic transfer hydrogenation with 1,4-cyclohexadiene

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by Plasma In Vitro and In Vivo to a Biologically Inactive Product Cleaved at the NH2 Terminus

Cleavage of protecting groups with boron tribromide

Defining minimal requirements for antibody production to peptide antigens.

The side chain of the proline residue in position 7 of oxytocin has been proposed as a binding site of the hormone for the uterotonic receptor. This is the first in a series of studies in which the possibility is explored that amino acid residues located at such sites and bearing unsaturated side chains may contribute more strongly to binding than neutral, aliphatic side chains. To test this hypothesis [7-(L-3,4-dehydroproline)]oxytocin, [1-beta-mecaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin, and [1-L-alpha-hydroxy-beta-mercaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin were prepared by the solid-phase technique of peptide synthesis. Some of the pharmacological properties of the analogues were determined, and the following specific activities, respectively, were found: rat uterotinic, 1071 +/- 59, 1066 +/- 95, 880 +/- 180; avian vasodepressor, 548 +/- 10, 1008 +/- 42, 1295 +/- 62; rat antidiuretic 5.9 +/- 0.2, 23.3 +/- 1.1, 76.7 +/- 2.3. All analogues possess a lower rat pressor activity than ocytocin. Compared to oxytocin, [7-(L-3,4,-dehydroproline)]oxytocin exhibits a parallel displacement of the cumulative uterotonic log dose vs. response curve toward lower concentration (pD2 = 9.26 vs. 8.63) but elicits the same maximum response. These data would seem to support the hypothesis that the introduction of unsatuation into binding element of a peptide hormone can enhance the affinity of the hormone for some of its receptors and thereby its selectivity.

Arthur M. Felix

Papers

Rapid removal of protecting groups from peptides by catalytic transfer hydrogenation with 1,4-cyclohexadiene

by Plasma In Vitro and In Vivo to a Biologically Inactive Product Cleaved at the NH2 Terminus

Cleavage of protecting groups with boron tribromide

Defining minimal requirements for antibody production to peptide antigens.

Pharmacological effects of introducing a double bond into a binding site of oxytocin. Analogues with L-3,4-dehydroproline in position 7.