Further US-patent issued
Fördermittelbescheid für die Biotechnologie-Firma Probiodrug AG
In a fruitful collaborative effort between the Max-Planck-Institute of Biochemistry, Proteros Biostructures GmbH, both located in Martinsried, and probiodrug AG, Halle (Saale), the sequence and 1.8 Å resolution crystal structure of native DP IV prepared from porcine kidney was determined. The crystal structure reveals a 2-2-2 symmetric tetrameric assembly which depends on the natively glycosylated beta-propeller blade IV. The crystal structure indicates that tetramerization of DP IV might be a key mechanism to regulate its interaction with other cellular components. Each subunit comprises two structural domains, the N-terminal eight-bladed beta-propeller with open Velcro topology and the C-terminal alpha/beta-hydrolase domain. A dipeptide mimicking inhibitor complexed to the active site discloses key determinants for substrate recognition, including a Glu-Glu motif that distinguishes DP IV as an aminopeptidase and an oxyanion trap that binds and activates the P2-carbonyl oxygen necessary for efficient postproline cleavage. The cyanopyrrolidine inhibitor is covalently forming an imidic acid ester with the active site serine of DP IV. In this paper (see the abstract) we discuss active site and non-active site-directed inhibition strategies of this pharmaceutical target protein.
About Probiodrug
AG Probiodrug is a biopharmaceutical company specialized on the development of innovative small molecule drugs for the treatment of neuronal, inflammatory, and autoimmune diseases. In these areas, Probiodrug is focusing on innovative targets with the prospect of first and best in class therapeutics. The Company has a dominant position in the area of glutaminyl cyclase inhibition, an enzyme central for the pathogenesis of AD. In this field, Probiodrug is pioneering a completely novel therapeutic approach. In addition, the company is pursuing further novel approaches in the area of inflammatory diseases. Probiodrug has generated evidence that glutaminyl cyclase, an enzyme that cyclizes N-terminal glutamine of peptides to pyroglutamate (pGlu), is massively overexpressed in the brain of patients with Alzheimer’s disease (AD). The company has also demonstrated that pyroglutamated derivatives of the amyloid beta (Aß) peptide are much more toxic and degradation-resistant than unmodified Aß peptides and that they form the very seeds of the typical Aß aggregates like AD plaques seen in the brain of AD patients. Moreover in animal models of AD, inhibitors of QC reduce both pGlu-Aß and total Aß, and improve memory. Probiodrug`s core expertise is based on its long-standing, unique experience with the structure and function elucidation of enzymes central for the maturation of hormones. The company has pioneered the field of DP4-inhibition for the treatment of type 2 diabetes. Compounds and technology patents of its DP4 (dipeptidyl peptidase 4) program in diabetes were licensed to various pharmaceutical companies. In 2004, all metabolic assets were sold to (OSI) Prosidion. The first drug based on Probiodrug`s technologies reached the market in late 2006. The proceeds of these transactions have been reinvested to fund the novel approach for the treatment of AD. The Company was founded in 1997 by Dr Konrad Glund and Prof Dr Hans-Ulrich Demuth and has raised a total of $52 million. In 2007, it acquired Ingenium Pharmaceuticals AG. The company is located in Halle (Saale), Germany, and operates a subsidiary in Martinsried/Munich, Germany.
For more information, please visit www.probiodrug.de.
Probiodrug AG
Dr Konrad Glund, CEO
Weinbergweg 22
D-06120 Halle (Saale)
Germany
Tel.: +49 345 55599-00
Fax: +49 345 55599-01
Mail: konrad.glund@probiodrug.de
akampion
Dr Ludger Weß
Saseler Loge 6b
D-22393 Hamburg
Germany
Tel.: +49 40 88 16 59 64
Fax: +49 40 88 16 59 65
Mail: ludger@akampion.com