Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development.

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2.

Oxidation of the Mycobacterium tuberculosis key virulence factor protein tyrosine phosphatase A (MptpA) reduces its phosphatase activity.

The Mycobacterium tuberculosis tyrosine-specific phosphatase MptpA and its cognate kinase PtkA are prospective targets for anti-tuberculosis drugs as they interact with the host defense response within the macrophages. Although both are structurally well-characterized, the functional mechanism regulating their activity remains poorly understood. Here, we investigate the effect of post-translational oxidation in regulating the function of MptpA.

Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex-vivo structural probing experiments.

F NMR-Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter-Screens.

We report here the nuclear magnetic resonance F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted.

The domain architecture of PtkA, the first tyrosine kinase from , differs from the conventional kinase architecture.

The discovery that MptpA (low-molecular-weight protein tyrosine phosphatase A) from () has an essential role for virulence has motivated research of tyrosine-specific phosphorylation in and other pathogenic bacteria. The phosphatase activity of MptpA is regulated via phosphorylation on Tyr and Tyr Thus far, only a single tyrosine-specific kinase, protein-tyrosine kinase A (PtkA), encoded by the gene has been identified within the genome. MptpA undergoes phosphorylation by PtkA.

Structural characterization of the intrinsically disordered domain of Mycobacterium tuberculosis protein tyrosine kinase A.

Although intrinsically disordered proteins or protein domains (IDPs or IDD) are less abundant in bacteria than in eukaryotes, their presence in pathogenic bacterial proteins is important for protein-protein interactions. The protein tyrosine kinase A (PtkA) from Mycobacterium tuberculosis possesses an 80-residue disordered region (IDD ) of unknown function, located N-terminally to the well-folded kinase core domain. Here, we characterize the conformation of IDD under varying biophysical conditions and phosphorylation using NMR-spectroscopy.