The human body harbours unsuspected resources. It also produces customised drugs such as peptides. Although this sounds like a far too bold hypothesis, it is not. Researchers from Ulm consider the approach so promising that they have now established the Ulm Centre for Peptide Pharmaceuticals (UPEP).
The UPEP aims to modify human peptides in such a way as to make them suitable as drugs. The centre will also assist small companies in developing peptides into marketable drug candidates and hopes that start-up companies will be established as a result. Grant proposals are currently being prepared, including a proposal seeking funds for the establishment of a cooperative research centre that will focus on basic research and a proposal for a project under the BMBF’s “Next generation of biotechnological methods 2020+” funding programme that will focus more on applied aspects.
The UPEP sees itself as a regional initiative; in addition to researchers from Ulm, it also involves researchers from the Faculty of Pharmaceutical Biotechnology at Biberach University of Applied Sciences around 40 km from Ulm. The reputed peptide pioneer Wolf-Georg Forssmann has moved from Hanover to Ulm and the centre can also count on the support of the regional pharmaceutical industry, including Rentschler Biotechnologie and Boehringer Ingelheim.
The establishment of the UPEP, which was officially opened in July 2013, was initiated by four scientists from Ulm University: Tanja Weil, Frank Kirchhoff, Jan Münch and Frank Rosenau. The centre is already well past the virtual network stage and projects are underway: the researchers are working on the establishment of peptide libraries from body liquids such as sweat, semen and bronchial lavage, and several research groups are engaged in testing peptides from Forssmann’s haemofiltrate library for their suitability as drugs for the treatment of infections and cancer. Haemofiltrate, which is the liquid resulting from the filtering of the blood of dialysis patients, has the same protein, peptide and amino acid composition as blood plasma and is available in large quantities.
Academic excellence, technological know-how, industry experience and interdisciplinary thinking – the UPEP spokesperson Dr. Frank Rosenau is convinced that the group of four founders brings together all the elements required to successfully run the centre:
Frank Rosenau comes from the Jülich Research Centre where he spent several years at the Biotech Institute carrying out many projects with industrial partners. The microbiologist brings his expertise to the centre where he will create recombinant peptide libraries and contribute his know-how in protein design and optimisation to the UPEP.
The chemist Tanja Weil from the Institute of Organic Chemistry III has in-depth knowledge of the drug discovery process in the pharmaceutical industry. Before joining the University of Ulm, Weil spent six years as the head of R&D at a German pharmaceutical company. Her research is located at the boundaries of biology, medicine and the material sciences. She aims to use customised biopolymers to optimise the transport of drugs into human cells.
In their search for antiviral compounds, the two virologists of the UPEP founding team, Frank Kirchhoff and Jan Münch, have identified, characterised and optimised a number of bioactive human peptides. Working with Forssmann and Reinhold Schmidt from the Hanover Medical School, the two AIDS researchers have shown a particular natural human peptide to be an effective HIV-1 inhibitor. Moreover, the two researchers have for many years been involved in screening human peptide libraries for novel viral inhibitors.
The centre brings together around 100 people from the laboratories of the four UPEP founders. In addition, the University of Ulm has created a senior professorship for Wolf-Georg Forssmann who plans to continue his life’s work in Ulm. In addition to technical equipment and material, Forssmann has also brought a group of scientists to the laboratory on the Eselsberg Ulm University campus. The UPEP strengthens and intensifies the university’s existing cooperations with the regional biopharmaceutical industry and Biberach University of Applied Sciences. Forssmann, who pioneered the search for natural peptide drugs around 20 years ago, has since placed a therapeutic peptide (urodilatin) on the market. “The time is now ripe to have a closer look at these protein degradation products,” said UPEP spokesperson Dr. Rosenau. Peptides can be generated following either one or two complementary possibilities, i.e. the degradome and recombinant peptide libraries.
The researchers from Ulm define degradome as the complete repertoire of peptides arising from the proteolytic degradation of proteins. Around 600 proteases exhibit their activity in virtually all cell cycle stages, wound healing, immune responses, blood coagulation and other physiological and pathophysiological processes. This makes the substance class of peptides highly interesting for the therapy of many diseases. Researchers are repeatedly making discoveries that substantiate the UPEP’s hypothesis that the human peptidome harbours many pharmacological “raw diamonds”. Ludger Ständker, a medical specialist from Hanover who is now in Ulm, has discovered that the LEKTI protein’s sole function is to be cleaved into smaller functional fragments by proteases; these peptides have different effects on target enzymes. Another example that substantiates the UPEP’s hypothesis is the human angiotensin-(1-7) heptapeptide. It results from the proteolytic cleavage of angiotensin I and has been found to protect against lung failure (Critical Care Medicine 8/2013, Walther T/Kübler W.: Angiotensin-(1-7) Protects From Experimental Acute Lung Injury).Peptides produced by the body itself hardly ever trigger an immune response, in total contrast to peptides derived from other sources. The UPEP is only interested in extracellular peptides, not in intracellular ones, which are difficult to extract and investigate. “We investigate what we find,” said Rosenau describing the UPEP’s approach.
Peptides are relatively unsuitable as drugs despite having some advantages over low-molecular compounds or antibodies. This is because smaller proteins (proteins up to 100 amino acids long are regarded as peptides) are quickly degraded by proteases and excreted from the body. Many researchers are therefore working on the development of technologies that are able to compensate for these disadvantages, generating peptides that have a greater resistance to proteolytic degradation, a higher serum half-life and that can be transported effectively across the cell membrane.The Faculty of Chemistry at Ulm University, with Mika Lindén (Department of Inorganic Chemistry II), Sven Rau (Department of Inorganic Chemistry II) and Tanja Weil from the Department of Organic Chemistry III, has outstanding knowledge of the material sciences. Rosenau therefore believes that the chemists will be able to turn proteins into pharmacologically active substances. The ideal scenario for the researchers from Ulm and other research institutions around the world is to be able to turn these biologicals into a pill form that prevents them from being broken down by the body in the gut, thereby obviating the need to inject them. Therapeutic peptides have recently undergone a true renaissance. Their chemical composition no longer appears to prevent their therapeutic success and they can be used for a broad range of therapeutic applications. There are 80 peptide drugs currently on the market and there are an estimated 200 in clinical and 400 in preclinical development phases.
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