Described here is a new class of peptidyl-oligonucleotide conjugates (POCs) which show efficient cleavage of a target RNA in a sequence-specific manner. Through phosphoramidate attachment of a 17-mer TΨC-targeting oligonucleotide to amphiphilic peptide sequences containing leucine, arginine, and glycine, zero-linker conjugates are created which exhibit targeted phosphodiester cleavage under physiological conditions. tRNA(Phe) from brewer's yeast was used as a model target sequence in order to probe different structural variants of POCs in terms of selective TΨC-arm directed cleavage. Almost quantitative (97-100%) sequence-specific tRNA cleavage is observed for several POCs over a 24 h period with a reaction half-life of less than 1 h. Nontargeted cleavage of tRNA(Phe) or HIV-1 RNA is absent. Structure-activity relationships reveal that removal of the peptide's central glycine residue significantly decreases tRNA cleavage activity; however, this can be entirely restored through replacement of the peptide's C-terminal carboxylic acid group with the carboxamide functionality. Truncation of the catalytic peptide also has a detrimental effect on POC activity. Based on the encouraging results presented, POCs could be further developed with the aim of creating useful tools for molecular biology or novel therapeutics targeting specific messenger, miRNA, and genomic viral RNA sequences.

Condensation between indole, Meldrum’s acid, and benzyloxycarbonylacetaldehyde or aminoacetaldehyde derivatives yielded trimolecular adducts 7a−c. The latter were cyclized to indole‐substituted 2‐pyrrolidones 15a−b or 3‐aminopyrrolid‐2‐ones 18a−b, depending on the starting material. Derivative 18a was transformed into pyrrolo[3′,4′:5,6]pyrido[3,4‐b]indol‐3(2H)‐ones 19a and 20a by a Pictet−Spengler condensation with benzaldehyde.

Neurotensin(8–13) analogues were biologically stabilised by replacement of the peptide bond between amino acids 8 and 9 by the reduced ψ(CH2‐NH) isostere. Diethylenetriaminepentaacetic acid (DTPA) analogues for In‐111 labelling and 2‐bromo‐phenyl‐acetyl analogues for radioiodination, showed receptor affinities in the nanomolar range in combination with a biological half life in human plasma up to 275 minutes. Biodistribution studies in male Wistar rats of metabolically stabilised and non‐stabilised 111In‐DTPA‐NT(8–13) analogues showed a major clearance from the blood through the kidneys. 125I‐Labelled neurotensin (8–13) analogues showed accumulation up to 2.2% of the injected dose per g tissue in the liver which might be an important disadvantage when diagnosis of tumours in the gut is aimed. Neurotensin(8–13) analogues labelled with In‐111 or I‐123 may act as new potential peptidergic radiopharmaceuticals for SPET diagnosis of neurotensin receptor (NTR) positive tumours. Copyright © 1999 John Wiley & Sons, Ltd.

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