12 research outputs found
Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands
Chemotherapy with
platinum complexes is essential for clinical
anticancer therapy. However, due to side effects and drug resistance,
further drug improvement is urgently needed. Herein, we report on
triple-action platinumÂ(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory
ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structureâactivity
relationship analysis showed that the mode of 1-MDT conjugation distinctly
impacts the reducibility and thus activation of the prodrugs. This
in turn affected ligand release, pharmacokinetic properties, efficiency
of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could
demonstrate that the design of albumin-targeted multi-modal prodrugs
using platinumÂ(IV) is a promising strategy to enhance the cellular
uptake of bioactive ligands with low cell permeability (1-MDT) and
to improve their selective delivery into the malignant tissue. This
will allow tumor-specific anticancer therapy supported by a favorably
tuned immune microenvironment
A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data
MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganismsâ role in ecology and human health
The replicative helicase MCM recruits cohesin acetyltransferase ESCO2 to mediate centromeric sister chromatid cohesion.
Chromosome segregation depends on sister chromatid cohesion which is established by cohesin during DNA replication. Cohesive cohesin complexes become acetylated to prevent their precocious release by WAPL before cells have reached mitosis. To obtain insight into how DNA replication, cohesion establishment and cohesin acetylation are coordinated, we analysed the interaction partners of 55 human proteins implicated in these processes by mass spectrometry. This proteomic screen revealed that on chromatin the cohesin acetyltransferase ESCO2 associates with the MCM2-7 subcomplex of the replicative Cdc45-MCM-GINS helicase. The analysis of ESCO2 mutants defective in MCM binding indicates that these interactions are required for proper recruitment of ESCO2 to chromatin, cohesin acetylation during DNA replication, and centromeric cohesion. We propose that MCM binding enables ESCO2 to travel with replisomes to acetylate cohesive cohesin complexes in the vicinity of replication forks so that these complexes can be protected from precocious release by WAPL Our results also indicate that ESCO1 and ESCO2 have distinct functions in maintaining cohesion between chromosome arms and centromeres, respectively