Publications by authors named "Gesa Volkers"

Article Synopsis
  • Bispecific antibodies (bsAbs) and multispecific antibodies (msAbs) can target multiple regions on a disease-causing agent, offering new treatment options for hard-to-treat diseases.
  • Early evaluation of these antibodies helps identify the ones with the highest potential for development, while dismissing those that are less promising.
  • Key factors such as molecular structure, risk of immune response, specificity, stability, and production capacity must be carefully assessed to ensure these therapies meet competitive standards.
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Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert).

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Propionibacterium acnes, though generally considered part of the normal flora of human skin, is an opportunistic pathogen associated with acne vulgaris as well as other diseases, including endocarditis, endophthalmitis and prosthetic joint infections. Its virulence potential is also supported by knowledge gained from its sequenced genome. Indeed, a vaccine targeting a putative cell wall-anchored P.

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Polysialyltransferases synthesize polysialic acid on cell surface-expressed glycoconjugates, which is crucial for developing processes and signaling pathways in eukaryotes. Recent advances in cancer research have rendered polysialyltransferases important drug targets because polysialic acid contributes to cancer cell progression, metastasis, and treatment of resistant tumors. To aid the development of high-throughput screening assays for polysialyltransferase inhibitors, we demonstrate that a previously developed class of fluorescent CMP-sialic acid mimetics for sialyltransferases has nanomolar affinities for oligo- and polysialyltransferases and can be used for the rapid screening of new polysialyltransferase inhibitors.

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Polysialic acid (polySia) is a homopolymeric saccharide that is associated with some neuroinvasive pathogens and is found on selective cell types in their eukaryotic host. The presence of a polySia capsule on these bacterial pathogens helps with resistance to phagocytosis, cationic microbial peptides and bactericidal antibody production. The biosynthesis of bacterial polySia is catalysed by a single polysialyltransferase (PST) transferring sialic acid from a nucleotide-activated donor to a lipid-linked acceptor oligosaccharide.

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Sialyltransferases of the mammalian ST8Sia family catalyze oligo- and polysialylation of surface-localized glycoproteins and glycolipids through transfer of sialic acids from CMP-sialic acid to the nonreducing ends of sialic acid acceptors. The crystal structure of human ST8SiaIII at 1.85-Å resolution presented here is, to our knowledge, the first solved structure of a polysialyltransferase from any species, and it reveals a cluster of polysialyltransferase-specific structural motifs that collectively provide an extended electropositive surface groove for binding of oligo-polysialic acid chain products.

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Expression of the aromatic hydroxylase TetX under aerobic conditions confers bacterial resistance against tetracycline antibiotics. Hydroxylation inactivates and degrades tetracyclines, preventing inhibition of the prokaryotic ribosome. X-ray crystal structure analyses of TetX in complex with the second-generation and third-generation tetracyclines minocycline and tigecycline at 2.

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Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions.

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The flavin-dependent monooxygenase TetX confers resistance to all clinically relevant tetracyclines, including the recently approved, broad-spectrum antibiotic tigecycline (Tygacil®) which is a critical last-ditch defense against multidrug-resistant pathogens. TetX represents the first resistance mechanism against tigecycline, which circumvents both the tet-gene encoded resistances, relying on active efflux of tetracyclines, and ribosomal protection proteins. The alternative enzyme-based mechanism of TetX depends on regioselective hydroxylation of tetracycline antibiotics to 11a-hydroxy-tetracyclines.

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The flavin-dependent monooxygenase TetX2 from Bacteroides thetaiotaomicron confers resistance against tetracyclines in aerobically grown Escherichia coli. TetX2 modifies several tetracycline antibiotics by regioselective hydroxylation of the substrates to 11a-hydroxy-tetracyclines. X-ray diffraction data were collected from a native TetX2 crystal and a TetX2 crystal with incorporated selenomethionine to resolutions of 2.

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