No abstract

Kinetic studies on enamine catalysis provided insight into the rate determining step(s) of peptide catalyzed conjugate addition reactions between aldehydes and nitroolefins. They demonstrate that not enamine formation but both the reaction of the enamine with the electrophile and hydrolysis of the resulting imine are rate limiting. These results allowed for reducing the catalyst loading by a factor of 10 to as little as 0.1 mol %. This is the lowest catalyst loading that has been achieved so far in enamine catalysis with low molecular weight catalysts for a broad range of substrates.

No abstract

Transcripts for α9 and α10 nicotinic acetylcholine receptor (nAChR) subunits are found in diverse tissues. The function of α9α10 nAChRs is best known in mechanosensory cochlear hair cells, but elsewhere their roles are less well-understood. α9α10 nAChRs have been implicated as analgesic targets and α-conotoxins that block α9α10 nAChRs produce analgesia. However, some of these peptides show large potency differences between species. Additionally several studies have indicated that these conotoxins may also activate GABAB receptors (GABABRs). To further address these issues, we cloned the cDNAs of mouse α9 and α10 nAChR subunits. When heterologously expressed in Xenopus oocytes, the resulting α9α10 nAChRs had the expected pharmacology of being activated by acetylcholine and choline but not by nicotine. A conotoxin analog, RgIA4, potently, and selectively blocked mouse α9α10 nAChRs with low nanomolar affinity indicating that RgIA4 may be effectively used to study murine α9α10 nAChR function. Previous reports indicated that RgIA4 attenuates chemotherapy-induced cold allodynia. Here we demonstrate that RgIA4 analgesic effects following oxaliplatin treatment are sustained for 21 days after last RgIA4 administration indicating that RgIA4 may provide enduring protection against nerve damage. RgIA4 lacks activity at GABAB receptors; a bioluminescence resonance energy transfer assay was used to demonstrate that two other analgesic α-conotoxins, Vc1.1 and AuIB, also do not activate GABABRs expressed in HEK cells. Together these findings further support the targeting of α9α10 nAChRs in the treatment of pain.

Metallized scaffolds: Oligoproline scaffolds that are functionalized with aldehyde groups have been shown to control the size of silver nanoparticles that are formed in the Tollens reaction. The size of the nanoparticles correlates linearly with the length of the scaffold and the oxidation of the aldehyde moieties during the reaction helps to stabilize the nanoparticles through coordination to the newly formed carboxylic acid groups.

Silver nanoparticles (AgNPs) are becoming increasingly important for manifold applications in, for example, imaging, catalysis, electronics, and the development of antimicrobial coatings. [1][2][3] The formation of AgNPs is typically accomplished by chemical reduction or irradiation of Ag + ions with visible light in the presence of additives, such as polymers or surfactants, which induce the formation of AgNPs and stabilize the NPs. [1,2] Recently, peptides bearing functional groups that coordinate to Ag + ions have become popular as additives. [4][5][6][7][8] Their large structural and functional diversity also renders peptides attractive for the controlled formation of AgNPs of defined sizes, which still presents a challenge to date. Since the rational design of peptides that induce metal NP formation is difficult, combinatorial approaches are attractive for the identification of suitable peptides. [7,8] We envisaged that colorimetric on-bead screening of split-andmix libraries could be a particularly powerful tool that would allow the testing of diverse libraries, which contain both natural and unnatural amino acids. [9] The typical size-and shape-dependent coloration of AgNPs [1] was anticipated to allow for a facile identification of active library members.Herein, we introduce the use of combinatorial split-andmix libraries for the identification of peptides that are capable of inducing the formation of AgNPs. In conjunction with scanning electron microscopy (SEM) studies, we also demonstrate that the method allows for the identification of certain types of peptides that induce the formation of AgNPs of specific sizes.We started our investigations by testing the members of peptide library 1 for their ability to induce AgNP formation in the presence of either light or the chemical reducing agent sodium ascorbate (Figure 1 a). Within the library, the amino acids serine (Ser), aspartic acid (Asp), histidine (His), and tyrosine (Tyr), bearing functional groups that were envisaged for Ag + ion coordination, were employed in positions AA1 and AA2 (Figure 1). Tyr was included in the library as it is a well-known photoactive residue. [6] Linkers of varying flexibility and geometry were used to connect the amino acids in order to allow for diverse spatial arrangements of their sidechain functional groups. trans-2-Aminohexanoic acid (Achc), Pro-Aib (Aib = aminoisobutyric acid) and Pro-Gly were chosen as turn-inducing linkers, and 6-aminohexanoic acid (Ahx) and b-alanine as flexible linkers. The library was prepared by encoded [10] split-and-mix synthesis [11] on TentaGel resin by utilizing seven different linkers and seven different l-and d-amino acids in positions AA1 and AA2, hence the library consisted maximally of 7 3 = 343 different peptides (Figure 1 a). Amino acid couplings were performed by following the standard Fmoc/tBu protocol for peptide synthesis using HBTU/iPr 2 NEt as the coupling reagent and piperidine for Fmoc deprotections (Fmoc = 9-fluorenylmethyloxycarbonyl, HBTU = O-(benzotriazol-l-yl)-N,N,N'...

This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.

Abstract. Disulfide bonds are post-translationnal modifications that can be crucial for the stability and the biological activities of natural peptides. Considering the importance of these disulfide bond-containing peptides, the development of new techniques in order to characterize these modifications is of great interest. For this purpose, collision cross cections (CCS) of a large data set of 118 peptides (displaying various sequences) bearing zero, one, two, or three disulfide bond(s) have been measured in this study at different charge states using ion mobility-mass spectrometry. From an experimental point of view, CCS differences (ΔCCS) between peptides bearing various numbers of disulfide bonds and peptides having no disulfide bonds have been calculated. The ΔCCS calculations have also been applied to peptides bearing two disulfide bonds but different cysteine connectivities (Cys1-Cys2/Cys3-Cys4; Cys1-Cys3/Cys2-Cys4; Cys1-Cys4/Cys2-Cys3). The effect of the replacement of a proton by a potassium adduct on a peptidic structure has also been investigated.