Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β-Lactam Antibiotics.

Antibiotic-resistant enterococci represent a significant global health challenge. Unfortunately, most β-lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β-lactam antibiotics.

Oral Delivery of the Vancomycin Derivative FU002 by a Surface-Modified Liposomal Nanocarrier.

Oral delivery of peptide therapeutics faces multiple challenges due to their instability in the gastrointestinal tract and low permeation capability. In this study, the aim is to develop a liposomal nanocarrier formulation to enable the oral delivery of the vancomycin-peptide derivative FU002. FU002 is a promising, resistance-breaking, antibiotic which exhibits poor oral bioavailability, limiting its potential therapeutic use.

Improved pharmacokinetics and enhanced efficacy of the vancomycin derivative FU002 using a liposomal nanocarrier.

Antibiotic resistance still represents a global health concern which diminishes the pool of effective antibiotics. With the vancomycin derivative FU002, we recently reported a highly potent substance active against Gram-positive bacteria with the potential to overcome vancomycin resistance. However, the translation of its excellent antimicrobial activity into clinical efficiency could be hampered by its rapid elimination from the blood stream.

Non-cross-linking advanced glycation end products affect prohormone processing.

Advanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones.

Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics.

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics.

Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci.

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented.

Development of Novel PSMA Ligands for Imaging and Therapy with Copper Isotopes.

Prostate-specific membrane antigen (PSMA)-binding tracers have been shown to be promising agents for the specific targeting of prostate tumors. On labeling with the short-lived isotopes F and Ga, excellent molecular imaging performance is achieved. This potential could be further exploited using long-lived isotopes.

A scavenger peptide prevents methylglyoxal induced pain in mice.

The reactive metabolite methylglyoxal (MG) has been identified as mediator of pain. Scavenging of free MG and the prevention of MG-derived post-translational modifications may provide a useful therapeutic treatment. An arginine-rich, fatty acid coupled, cyclic peptide (CycK(Myr)R4E) with high proteolytic stability and prolonged circulation was developed for the scavenging of MG.

Renal Targeting: Peptide-Based Drug Delivery to Proximal Tubule Cells.

Kidney-specific drug targeting is an attractive strategy to reduce unwanted side effects and to enhance drug efficacy within the renal tissue. For this purpose a novel kidney-specific drug carrier was developed. The peptide sequence (KKEEE)3K triggers exceptional renal specificity at high accumulation rates.

Radiopharmaceutical therapy of patients with metastasized melanoma with the melanin-binding benzamide 131I-BA52.

Unlabelled: The performance of cytotoxic drugs is defined by their selectivity of uptake and action in tumor tissue. Recent clinical responses achieved by treating metastatic malignant melanoma with therapeutic modalities based on gene expression profiling showed that malignant melanoma is amenable to systemic treatment. However, these responses are not persistent, and complementary targeted treatment strategies are required for malignant melanoma.

The pharmacokinetics of cell-penetrating peptides.

Cell-penetrating peptides (CPPs) are able to penetrate the cell membrane carrying cargoes such as peptides, proteins, oligonucleotides, siRNAs, radioisotopes, liposomes, and nanoparticles. Consequently, many delivery approaches have been developed to use CPPs as tools for drug delivery. However, until now a systematic analysis of their in vivo properties including potential tumor binding specificity for drug targeting purposes has not been conducted.

PAMAM structure-based multifunctional fluorescent conjugates for improved fluorescent labelling of biomacromolecules.

Fluorescent probes are of increasing interest in medicinal and biological applications for the elucidation of the structures and functions of healthy as well as tumour cells. The quality of these investigations is determined by the intensity of the fluorescence signal. High dye/carrier ratios give strong signals.

Fluorescent somatostatin receptor probes for the intraoperative detection of tumor tissue with long-wavelength visible light.

Targeted fluorescent dyes are of substantial value for the intraoperative delineation of primary tumors and metastatic lesions. For this purpose long-wavelength red light (lambda=550-650 nm) offers advantages because of good tissue penetration and direct visibility. Since somatostatin receptors (SSTR) are overexpressed in a number of tumors, a series of potentially tumor-selective peptide-dye conjugates were synthesized by solid-phase peptide synthesis (SPPS).

Influence of transfer RNA tertiary structure on aminoacylation efficiency by glutaminyl and cysteinyl-tRNA synthetases.

The position of the tertiary Levitt pair between nucleotides 15 and 48 in the transfer RNA core region suggests a key role in stabilizing the joining of the two helical domains, and in maintaining the relative orientations of the D and variable loops. E. coli tRNA(Gln) possesses the canonical Pu15-Py48 trans pairing at this position (G15-C48), while the tRNA(Cys) species from this organism instead features an unusual G15-G48 pair.

Fast and simple purification of chemically modified hammerhead ribozymes using a lipophilic capture tag.

A new type of 5'-lipophilic capture tag is described, enabling the facile reverse phase HPLC purification of chemically modified hammerhead ribozymes (oligozymes) whilst still carrying the 2'-O-tert.-butyldimethylsilyl protection of the essential riboses. In its most convenient form, the capture tag consists of a simple diol, such as hexan-1,6-diol, which at one end is attached via a silyl residue to a highly lipophilic entity such as tocopherol (vitamin E) or cholesterol, and the other end is functionalized as a phosphoramidite.

Identification of four Borrelia burgdorferi sensu lato species in Ixodes ricinus ticks collected from Dutch dogs.

The prevalence of Borrelia species infection was determined by polymerase chain reaction (PCR) in 138 ticks collected from dogs which were walked regularly in the wooded areas near the city of Eindhoven, the Netherlands. The PCR amplified the spacer region between the 5S and 23 S rRNA genes, and the Borrelia species was identified by hybridization with specific probes. Borrelia burgdorferi sensu lato was present in 20 of 138 (14.

How glutaminyl-tRNA synthetase selects glutamine.

Background: Aminoacyl-tRNA synthetases covalently link a specific amino acid to the correct tRNA. The fidelity of this reaction is essential for accurate protein synthesis. Each synthetase has a specific molecular mechanism to distinguish the correct pair of substrates from the pool of amino acids and isologous tRNA molecules.

Pharmacokinetics of a synthetic, chemically modified hammerhead ribozyme against the rat cytochrome P-450 3A2 mRNA after single intravenous injections.

Modulation of gene expression via nucleic acid sequence-specific intervention represents a new paradigm for drug discovery and development. Ribozymes are small RNA structures capable of cleaving RNA target molecules in a catalytic fashion. A 2'-O-allyl-modified hammerhead ribozyme designed to cleave the messenger RNA of cytochrome P-450 3A2 was administered to rats via 0.

Crystal structures at 2.5 angstrom resolution of seryl-tRNA synthetase complexed with two analogs of seryl adenylate.

Crystal structures of seryl-tRNA synthetase from Thermus thermophilus complexed with two different analogs of seryl adenylate have been determined at 2.5 A resolution. The first complex is between the enzyme and seryl-hydroxamate-AMP (adenosine monophosphate), produced enzymatically in the crystal from adenosine triphosphate (ATP) and serine hydroxamate, and the second is with a synthetic analog of seryl adenylate (5'-O-[N-(L-seryl)-sulfamoyl]adenosine), which is a strong inhibitor of the enzyme.

New synthetic routes to synthons suitable for 2'-O-allyloligoribonucleotide assembly.

New synthetic routes have been devised for the high yield preparation of protected 2'-O-allylribonucleoside-3'-O-phosphoramidites, exemplified by the ribonucleosides guanosine and 2,6-diaminopurine riboside (2-aminoadenosine). Key features are the use of versatile intermediates and an easy allylation step. The development of a novel synthon based on 2'-O-allyl-2,6-diaminopurine riboside enables short 2'-O-allyl-oligoribonucleotide probes to be synthesized with adenine replaced by 2-aminoadenine.

2'-O-alkyloligoribonucleotides, synthesis and applications in molecular biology.

Oligo(2'-O-alkylribonucleotides) have been synthesized in which alkyl is methyl, allyl and butyl. The various phosphoramidite monomers of 2'-O-alkyl uridine, cytidine, adenosine, guanosine, inosine and 2,6-diaminopurine riboside have been synthesized from a minimum of key intermediates. Extra protection of the lactam function in uracil and hypoxanthine proves useful.

Synthesis and applications of oligoribonucleotides with selected 2'-O-methylation using the 2'-O-[1-(2-fluorophenyl)-4-methoxypiperidin-4-yl] protecting group.

The synthesis of base protected 5'-O-dimethoxytrityl-2'-O-[1-(2- fluorophenyl)-4-methoxypiperidin-4-yl]-3'-O-(2-cyanoethyl N,N-diisopropylphosphoramidites) is described, using phenoxyacetyl protection for the exocyclic amino groups of guanosine and adenosine and acetyl protection of the amino group of cytidine. High yield assembly of these building blocks into oligoribonucleotides on aminopropyl controlled pore glass was achieved using 5-(4-nitrophenyl)-1H-tetrazole as activator. Mixed sequences containing selected 2'-O-methylation were also synthesised and their significance for the study of RNA biochemistry is discussed.

New synthetic routes to protected purine 2'-O-methylriboside-3'-O-phosphoramidites using a novel alkylation procedure.

A highly selective alkylation procedure has been developed enabling new synthetic routes to be established for protected purine 2'-O-methylriboside-3'-O-phosphoramidites; building blocks for the assembly of 2'-O-methyloligoribonucleotides. The new procedure avoids the use of the highly toxic and potentially explosive reagent diazomethane and is far superior to the use of silver oxide/methyl iodide. Moreover, the use of highly versatile key intermediates will enable the synthesis of a wide variety of base modified analogues as well as other 2'-O-alkylriboside derivatives.