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During the last decades, therapeutical proteins have risen to great significance in the pharmaceutical industry. As non-human proteins that are introduced into the human body cause a distinct immune system reaction that triggers their rapid clearance, most newly approved protein pharmaceuticals are shielded by modification with synthetic polymers to significantly improve their blood circulation time. All such clinically approved protein-polymer conjugates contain polyethylene glycol (PEG) and its conjugation is denoted as PEGylation. However, many patients develop anti-PEG antibodies which cause a rapid clearance of PEGylated molecules upon repeated administration. Therefore, the search for alternative polymers that can replace PEG in therapeutic applications has become important. In addition, although the blood circulation time is significantly prolonged, the therapeutic activity of some conjugates is decreased compared to the unmodified protein. The reason is that these conjugates are formed by the traditional conjugation method that addresses the protein's lysine side chains. As proteins have many solvent exposed lysines, this results in a somewhat uncontrolled attachment of polymer chains, leading to a mixture of regioisomers, with some of them eventually affecting the therapeutic performance.
This thesis investigates a novel method for ligating macromolecules in a site-specific manner, using enzymatic catalysis. Sortase A is used as the enzyme: It is a well-studied transpeptidase which is able to catalyze the intermolecular ligation of two peptides. This process is commonly referred to as sortase-mediated ligation (SML). SML constitutes an equilibrium reaction, which limits product yield. Two previously reported methods to overcome this major limitation were tested with polymers without using an excessive amount of one reactant.
Specific C- or N-terminal peptide sequences (recognition sequence and nucleophile) as part of the protein are required for SML. The complementary peptide was located at the polymer chain end. Grafting-to was used to avoid damaging the protein during polymerization. To be able to investigate all possible combinations (protein-recognition sequence and nucleophile-protein as well as polymer-recognition sequence and nucleophile-polymer) all necessary building blocks were synthesized. Polymerization via reversible deactivation radical polymerization (RDRP) was used to achieve a narrow molecular weight distribution of the polymers, which is required for therapeutic use.
The synthesis of the polymeric building blocks was started by synthesizing the peptide via automated solid-phase peptide synthesis (SPPS) to avoid post-polymerization attachment and to enable easy adaptation of changes in the peptide sequence. To account for the different functionalities (free N- or C-terminus) required for SML, different linker molecules between resin and peptide were used.
To facilitate purification, the chain transfer agent (CTA) for reversible addition-fragmentation chain-transfer (RAFT) polymerization was coupled to the resin-immobilized recognition sequence peptide. The acrylamide and acrylate-based monomers used in this thesis were chosen for their potential to replace PEG.
Following that, surface-initiated (SI) ATRP and RAFT polymerization were attempted, but failed. As a result, the newly developed method of xanthate-supported photo-iniferter (XPI) RAFT polymerization in solution was used successfully to obtain a library of various peptide-polymer conjugates with different chain lengths and narrow molar mass distributions.
After peptide side chain deprotection, these constructs were used first to ligate two polymers via SML, which was successful but revealed a limit in polymer chain length (max. 100 repeat units). When utilizing equimolar amounts of reactants, the use of Ni2+ ions in combination with a histidine after the recognition sequence to remove the cleaved peptide from the equilibrium maximized product formation with conversions of up to 70 %.
Finally, a model protein and a nanobody with promising properties for therapeutical use were biotechnologically modified to contain the peptide sequences required for SML. Using the model protein for C- or N-terminal SML with various polymers did not result in protein-polymer conjugates. The reason is most likely the lack of accessibility of the protein termini to the enzyme. Using the nanobody for C-terminal SML, on the other hand, was successful. However, a similar polymer chain length limit was observed as in polymer-polymer SML. Furthermore, in case of the synthesis of protein-polymer conjugates, it was more effective to shift the SML equilibrium by using an excess of polymer than by employing the Ni2+ ion strategy.
Overall, the experimental data from this work provides a good foundation for future research in this promising field; however, more research is required to fully understand the potential and limitations of using SML for protein-polymer synthesis. In future, the method explored in this dissertation could prove to be a very versatile pathway to obtain therapeutic protein-polymer conjugates that exhibit high activities and long blood circulation times.
Zuerst erschienen in:
Alexander von Humboldt-Stiftung. Mitteilungen, 5. Jg., Heft 38, Oktober 1980, S. 27–36.
Off-road adventures
(2024)
This article focuses on the visual qualities of Alexander von Humboldt’s statistical tables in his Political Essay on the Kingdom of New Spain (1808–1811, 2nd ed. 1825–1827) with special attention to how such composites of numbers, alphabetical script, and semiotic elements relate to narrative writing. I argue that Humboldt’s tables/tableaus open up spaces inside his narrative that fragment the reading process, inviting new conversations, connections, and ideas.
Die deutsch-kubanische Forschungs- und Digitalisierungsinitiative „Proyecto Humboldt Digital“ (ProHD) hat während ihrer Projektlaufzeit (2019–2023) wichtige Quellen zum Thema „Humboldt und Kuba“ erstmals digital erschlossen. Als Kooperation zwischen der Berlin-Brandenburgischen Akademie der Wissenschaften und der Oficina del Historiador de la Ciudad de La Habana hat ProHD damit wichtige Akzente für die Archivdigitalisierung, die digitale Editionsphilologie und die digitale Wissenschaftskommunikation in Kuba gesetzt. Das Korpus der erschlossenen Bestände wird hier in fünf Schlaglichtern vorgestellt: 1) Quellen zur Humboldt’schen Forschungsreise, 2) Juan Luis de la Cuesta, 3) Materialien zu Kuba aus dem Humboldt-Nachlass, 4) Zensur und Beschlagnahme des Essai politique sur l’île de Cuba, 5) Francisco de Arango y Parreño.
La traduction en langue chinoise du premier volume du monumental ouvrage scientifique d'Alexander von Humboldt, intitulé «Cosmos», a vu le jour en 2023 sous l՚égide de la prestigieuse maison d՚édition de l՚Université de Pékin. Dans sa postface éclairée, la traductrice émérite, Gao Hong, éclaire la lanterne des lecteurs chinois sur la fresque cosmique esquissée par Humboldt, révélant ainsi les intrications entre les phénomènes naturels et leur pertinence à l՚échelle de l'univers tout entier. Gao Hong narre son propre périple aux côtés de Humboldt, tout en distillant ses réflexions personnelles sur cette fresque cosmique. «Cosmos» d՚Humboldt, œuvre scientifique par excellence, transcende également les sphères esthétiques et artistiques, exprimant invariablement une profonde vénération pour l՚univers. Restituer en chinois la «beauté géométrique» de la langue allemande, empreinte d՚une rigueur structurelle, constitue un défi singulier, le chinois se caractérisant par sa fluidité, sa souplesse et sa poésie imagée, en totale antithèse avec l՚allemand. En qualité de traducteur, il importe de naviguer librement entre ces deux mondes linguistiques distincts.
In dem Aufsatz wird ein Brief erstmalig veröffentlicht, in dem Alexander von Humboldt im Jahr 1849 bei einem Minister der liberalen Regierung von Kurhessen die Verdienste eines an der Universität in Marburg lehrenden jungen Professors hervorhob. Die Rede ist hier von dem später durch bahnbrechende Entdeckungen berühmten Physiologen Carl Ludwig. Vermittelt wurde das Schreiben durch den Humboldt nahestehenden Mediziner und Physiologen Emil du Bois-Reymond. Der Empfehlungsbrief, mit dem Humboldt versuchte, Ludwigs finanzielle Situation zu verbessern, ist ein Beispiel für die Förderung junger Forscher wie auch freier wissenschaftlicher Institutionen durch Humboldt.