The main benefit of natural peptides, peptide analogs and newly designed peptides as therapeutics, lies in their high selectivity and affinity, which are frequently in the nanomolar range. New drugs targeting protein-protein interactions often require larger interaction sites than small molecules can offer. Thus, many peptidic drugs are already applied in therapy at the current state. The next generation of peptide-based therapeutic agents is currently on its way from basic research to clinical studies and eventually to the pharmaceutical market. Development of more robust and long-lasting drugs owing to well-known and new stabilization strategies is yielding novel and continuously improving peptide drugs. The introduction of smart linkers that exhibit stability towards blood plasma but intracellular lability will lead to target-oriented activity, which might successfully decrease side effects. In this review, peptidic therapeutics on the market, in clinical studies and some of those in basic research are characterized. Stabilization strategies and intelligent linkers are discussed with respect to their use in peptide drug therapy.

Nontoxic ortho-carbaborane is one of the most promising structure for boron neutron capture therapy (BNCT). For directed uptake of ortho-carbaborane by tumor cells, receptor-subtype selective neuropeptide Y (NPY) and its derivatives were modified with ortho-carbaborane. The derivative [F(7), P(34)]-NPY has been shown to be a breast cancer selective ligand that binds to the Y(1)-receptor subtype, whereas [Ahx(5-24)]-NPY selectively addresses Y(2)-receptor subtypes that are found in neuroblastoma cells. ortho-Carbaboranyl propionic acid was synthesized and linked to the ε-amino group of N(α)-Fmoc protected L-lysine. The characterization of the compounds was performed by NMR, IR, and MS studies. The carbaborane-modified amino acid was incorporated into NPY, [F(7), P(34)]-NPY, and [Ahx(5-24)]-NPY by an optimized solid phase peptide synthesis using Fmoc protection. Binding studies and IP accumulation assays confirmed nanomolar affinity and activity of the modified analogues despite of the large carbaborane cluster. Internalization studies revealed excellent and receptor subtype specific uptake of the conjugates into respective cells.

Peptidic ligands selectively targeting distinct G protein-coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor-preferring analogues of neuropeptide Y (NPY) bind and activate the human Y1 receptor subtype (hY1 receptor), which is found in 90% of breast cancer tissue and in all breast-cancer-derived metastases. Herein, novel highly boron-loaded Y1 -receptor-preferring peptide analogues are described as smart shuttle systems for carbaboranes as (10) B-containing moieties. Various positions in the peptide were screened for their susceptibility to carbaborane modification, and the most promising positions were chosen to create a multi-carbaborane peptide containing 30 boron atoms per peptide with excellent activation and internalization patterns at the hY1 receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi-carbaborane peptide into hY1 -receptor-expressing cells, exceeding the required amount of 10(9) boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron-containing moieties.

The cobalt bis(dicarbollide) complex [commo-3,3'-Co(1,2-C2 B9 H11 )2 ](-) has captured much attention in biochemical and medical contexts, in particular for the treatment of tumors by boron neutron capture therapy (BNCT). Derivatives of cobalt bis(dicarbollide) are commonly prepared through ring-opening reactions of cyclic oxonium ions, so the corresponding products are usually charged. Furthermore, attempts to incorporate cobalt bis(dicarbollide) into peptides are rare, despite obvious potential advantages. Here the synthesis of an imidazolium-based charge-compensated cobalt bis(dicarbollide) building block, which allows additional modifications with moieties of biochemical relevance, such as monosaccharides, is reported. Furthermore, conjugates of these building blocks with the Y1 -receptor-selective derivative of neuropeptide Y ([F(7) ,P(34) ]-NPY) retained excellent response to hY1 receptors found to be overexpressed in breast tumors and metastases.

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