Radiolabeling Strategies of Nanobodies for Imaging Applications

Nanobodies are small recombinant antigen-binding fragments derived from camelid heavy-chain only antibodies. Due to their compact structure, pharmacokinetics of nanobodies are favorable compared to full-size antibodies, allowing rapid accumulation to their targets after intravenous administration, while unbound molecules are quickly cleared from the circulation. In consequence, high signal-to-background ratios can be achieved, rendering radiolabeled nanobodies high-potential candidates for imaging applications in oncology, immunology and specific diseases, for instance in the cardiovascular system. In this review, a comprehensive overview of central aspects of nanobody functionalization and radiolabeling strategies is provided

Convergent Synthesis of Two Fluorescent Ebselen-Coumarin Heterodimers

The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes containing ebselen are expected to be suitable for further biological and medicinal studies. We therefore designed and synthesized two coumarin-tagged activity-based probes bearing the ebselen warhead. The heterodimers differ by the nature of the spacer structure, for which—in the second compound—a PEG/two-amide spacer was introduced. The interaction of this probe and of ebselen with two cysteine proteases was investigated

Study Protocol of a Prospective, Monocentric, Single-Arm Study Investigating the Safety and Efficacy of Local Ablation of Symptomatic Uterine Fibroids with US-Guided High-Intensity Focused Ultrasound (HIFU)

Uterine fibroids are the most common benign tumors of the uterus. Approximately 20–50% of women with myomas experience a variety of symptoms such as vaginal bleeding, abdominal pain, pelvic pain and pressure, and urological problems, possibly interfering with fertility and pregnancy. Although surgery remains the standard treatment option for fibroids, non-invasive therapeutic options, such as high-intensity focused ultrasound (HIFU), have emerged over the last dec ade. During HIFU, ultrasound is focused on the target tissue causing coagulation necrosis. HIFU has, meanwhile, become an established method for treating uterine fibroids in many countries. Clinical data have shown that it effectively alleviates fibroid-related symptoms and reduces fibroid size with a very low rate of side effects. However, there is a lack of data on how this treatment affects laboratory parameters and structural features of uterine tissue. As our center is the only one in German-speaking countries where ultrasound-guided HIFU technology is currently established, the aim of this prospective, monocentric, single-arm trial is not only to evaluate the safety and efficacy of local US-guided HIFU in symptomatic uterine fibroid patients according to GCP standards but also to explore its effects on blood parameters and the structural integrity of uterine tissue using elastographic methods

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

Number: 1 Publisher: Nature Publishing GroupThe potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products