A5061278872- Adenosine and Purinergic Signaling
- Neonatal Health and Biochemistry
- Protease and Inhibitor Mechanisms
- Biochemical and Molecular Research
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Calpain Protease Function and Regulation
- Cytomegalovirus and herpesvirus research
- Enzyme Production and Characterization
- Pneumocystis jirovecii pneumonia detection and treatment
- Clostridium difficile and Clostridium perfringens research
- Microbial Natural Products and Biosynthesis
- ATP Synthase and ATPases Research
- Bacterial Identification and Susceptibility Testing
- Neuropeptides and Animal Physiology
- Biochemical and Structural Characterization
- Glycosylation and Glycoproteins Research
- Calcium signaling and nucleotide metabolism
- Legionella and Acanthamoeba research
- Protein purification and stability
- Enzyme function and inhibition
- Enzyme Structure and Function
- Respiratory viral infections research
- Influenza Virus Research Studies
- Microbial Metabolic Engineering and Bioproduction
Helmholtz Centre for Infection Research
2017-2021
Leipzig University
2012-2020
ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used a lead structure, and derivatives modified in various positions were prepared. Products tested at rat recombinant eN. 6-(Ar)alkylamino substitution led largest improvement potency. N6-Monosubstitution superior symmetrical N6,N6-disubstitution....
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present synthesis, structure–activity relationships, and cocrystal structures novel derivatives competitive inhibitor α,β-methylene-ADP (AOPCP) substituted in 2-position. Small polar or lipophilic residues increased potency, 2-iodo- 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being most potent with Ki values toward human 3–6 nM. Subject to size nature 2-substituent, variable binding modes...
Abstract Ecto‐5′‐nucleotidase (CD73, EC 3.1.3.5) catalyzes the extracellular hydrolysis of AMP yielding adenosine, which induces immunosuppression, angiogenesis, metastasis, and proliferation cancer cells. CD73 inhibition is therefore proposed as a novel strategy for (immuno)therapy, antibodies are currently undergoing clinical trials. Despite considerable efforts, development small molecule inhibitors has met with limited success. To develop suitable drug candidate, high resolution (2.05 Å)...
SerpinA12 (vaspin) is thought to be mainly expressed in adipose tissue and has multiple beneficial effects on metabolic, inflammatory atherogenic processes related obesity. KLK7 (kallikrein 7) the only known protease target of vaspin date inhibited with a moderate inhibition rate. In crystal structure, cleavage site (P1-P1') reactive centre loop fairly rigid compared flexible residues before P2, possibly supported by an ionic interaction P1' glutamate (Glu(379)) arginine residue (Arg(302))...
Many members of the serine protease inhibitor (serpin) family are activated by glycosaminoglycans (GAGs). Visceral adipose tissue-derived serpin (vaspin), A12 family, and its target kallikrein 7 (KLK7) heparin-binding proteins, inhibition KLK7 vaspin is accelerated heparin. However, nature GAG binding to not known. Here, we measured various low molecular weight heparins microscale thermophoresis analyzed acceleration these molecules. In addition, basic residues contributing heparin...
Diffocins are high-molecular-weight phage tail-like bacteriocins (PTLBs) that some Clostridium difficile strains produce in response to SOS induction. Similar the related R-type pyocins from Pseudomonas aeruginosa, diffocins act as molecular puncture devices specifically penetrate cell envelope of other C. dissipate membrane potential and kill attacked bacterium. Thus, constitute therapeutic agents counter difficile-associated infections. PTLBs consist rigid contractile protein complexes....
The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous studies showed that cannot replicate efficiently in Tmprss2 −/− knock-out mice whereas viruses are able the same levels as wild type (WT) mice. Here, we investigated sequence requirements for HA molecule allow IAV absence TMPRSS2. We replacement H3 H1-loop (amino acids 320 329, at C-terminus 1 ) was not sufficient equal replication or severe pathology compared WT However,...
The serine protease kallikrein-related peptidase 7 (KLK7) is a member of the human tissue kallikreins. Its dysregulation leads to pathophysiological inflammatory processes in skin. Furthermore, it plays role several types cancer. For treatment KLK7-associated diseases, coumarinic esters have been developed as small-molecule enzyme inhibitors. To characterize inhibition mode these inhibitors, we analyzed structures inhibited by X-ray crystallography. Electron density shows inhibitors...
Abstract The adipokine vaspin (serpinA12) is mainly expressed in white adipose tissue and exhibits various beneficial effects on obesity-related processes. Kallikrein 7 the only known target protease of inhibited by classical serpin inhibitory mechanism involving a cleavage reactive center loop between P1 (M378) P1′ (E379). Here, we present X-ray structure vaspin, cleaved M378 E379. We provide comprehensive analysis differences uncleaved forms shutter, breach, hinge regions with relation to...
The virulence factor PlaB promotes lung colonization, tissue destruction, and intracellular replication of