Pharmacology, an innovative factor in therapeutic research

As members of the pharmacology training group set up by the committee of pharmacological science of the French Academy of Pharmacy, we examine the situation of pharmacology in drug discovery. Today, it is obvious that by integrating genome sequencing, cellular and molecular biology, and bioinformatics, pharmacology has become a cross-disciplinary science. Pharmacologists must become knowledgeable in a wide range of domains, using the major points in each to direct them towards the discovery and development of new therapeutic agents. It is also clear that pharmacology remains a major factor in the different steps of drug discovery, from the molecular and cellular stages, to clinical and pharmaceutical developments.     

Novel strategy in lupus therapy: from the peptide P140 to Lupuzor™

Autoimmune diseases are illnesses that occur when the body's tissues are attacked by its own immune system. This review describes the path between the discovery of a synthetic peptide able to delay the development of lupus in mouse models that spontaneously develop lupus-like disease, and the results of multicenter phase IIb clinical trials including lupus patients. If the 2nd phase IIb and phase III results confirm the 1st phase IIb clinical trial, this therapeutic peptide could have a major impact in the treatment of patients with lupus, an autoimmune disease affecting at least five million patients in the world, in majority young women for whom there is no specific treatment today.     

Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin binding site: structural characterisation of the related copper complex

Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N₂S₂ donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine.