A5027186713- Microtubule and mitosis dynamics
- Carbohydrate Chemistry and Synthesis
- 14-3-3 protein interactions
- Cancer therapeutics and mechanisms
- Microbial Natural Products and Biosynthesis
- Enzyme Structure and Function
- Chemical Synthesis and Analysis
- Glycosylation and Glycoproteins Research
- Synthesis and biological activity
- Photochromic and Fluorescence Chemistry
- Monoclonal and Polyclonal Antibodies Research
- Various Chemistry Research Topics
- Escherichia coli research studies
- Photoreceptor and optogenetics research
- Genetics, Aging, and Longevity in Model Organisms
- Cell Adhesion Molecules Research
- Bioactive Compounds and Antitumor Agents
- Crystallography and molecular interactions
- Computational Drug Discovery Methods
- Cancer Treatment and Pharmacology
- Protist diversity and phylogeny
- Photosynthetic Processes and Mechanisms
- Cancer Mechanisms and Therapy
- Antibiotic Resistance in Bacteria
- Telomeres, Telomerase, and Senescence
University of Basel
2017-2024
Paul Scherrer Institute
2018-2023
Micron (United States)
2021
Micron Biomedical (United States)
2021
Harm Reduction Services
2021
Robert Bosch (Germany)
2021
Albert Einstein College of Medicine
2020
Monell Chemical Senses Center
2020
University of Pennsylvania
2020
Kinesin-1 is responsible for microtubule-based transport of numerous cellular cargoes. Here, we explored the regulation kinesin-1 by MAP7 proteins. We found that all four mammalian family members bind to kinesin-1. In HeLa cells, MAP7, MAP7D1, and MAP7D3 act redundantly enable kinesin-1–dependent microtubule recruitment truncated KIF5B-560, which contains stalk but not cargo-binding autoregulatory regions. vitro, purified increase landing rate processivity through transient association with...
Abstract Tubulin plays essential roles in vital cellular activities and is the target of a wide range proteins ligands. Here, using combined computational crystallographic fragment screening approach, we addressed question how many binding sites exist tubulin. We identified 27 distinct sites, which 11 have not been described previously, analyzed their relationship to known tubulin–protein tubulin–ligand interactions. further observed an intricate pocket communication network 56 chemically...
The binding and release of ligands from their protein targets is central to fundamental biological processes as well drug discovery. Photopharmacology introduces chemical triggers that allow the changing ligand affinities thus activity by light. Insight into molecular mechanisms photopharmacology largely missing because relevant transitions during light-triggered reaction cannot be resolved conventional structural biology. Using time-resolved serial crystallography at a synchrotron X-ray...
Paclitaxel (Taxol) is a taxane and chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules well described, lack high-resolution structural information on tubulin-taxane complex precludes comprehensive description binding determinants affect its mechanism action. Here, we solved crystal structure baccatin III core moiety paclitaxel-tubulin at 1.9 Å resolution. Based this information, engineered taxanes modified C13 side chains, their...
Abstract Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti‐adhesive approach targeting FimH, bacterial lectin enabling attachment E. coli to host cells, attracted considerable interest. FimH can adopt low/medium‐affinity state in absence and high‐affinity presence shear forces. Until recently, mostly been investigated, despite fact that therapeutic antagonist should bind predominantly low‐affinity state....
In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells G2/M, induces cell death, synergizes vinblastine. The compound destabilizes microtubules by acting as molecular plug that sterically inhibits curved-to-straight conformational switch α-tubulin subunit,...
Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known date; however, their exact molecular mechanism of action remains unclear. Here, we present 2.2 Å resolution X-ray crystal structure a cryptophycin derivative bound αβ-tubulin heterodimer. The addresses conformational issues in previous 3.3 cryo-electron microscopy cryptophycin-52 maytansine site β-tubulin. It further provides atomic details on interactions cryptophycins, which had...
Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors pharmacologically relevant targets. In this contribution, we present application a bacterial target, lectin FimH, crucial virulence factor uropathogenic E. coli being main cause urinary tract infections. A small library acylhydrazones was formed from aldehydes and hydrazides equilibrated at neutral pH in presence aniline as nucleophilic catalyst. The major success...
It has been proposed that one of the mechanisms taxane-site ligand-mediated tubulin activation is modulation structure a switch element (the M-loop) from disordered form in dimeric to folded helical microtubules. Here, we used covalent ligands, including cyclostreptin, gain further insight into this mechanism. The crystal cyclostreptin-bound reveals binding βHis229, but no stabilization M-loop. capacity cyclostreptin induce microtubule assembly compared other agents demonstrates induction...
There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, MTH1 inhibitor prevents detoxification oxidized nucleotide triphosphates. This combination showed robust synergistic killing cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying mechanism, developed VISAGE, a...
The d-GlcNAc moiety in sialyl Lewisx (sLex, 1) acts predominantly as a linker to position the d-Gal and l-Fuc moieties bioactive spatial orientation. hypothesis has been made that NHAc group of GlcNAc pushes fucose underneath galactose and, thus, contributes stabilization conformation core sLex (1). To test this hypothesis, mimetics consisting (R,R)-1,2-cyclohexanediols substituted with alkyl aryl substituents adjacent linking were synthesized. explore broad range extended spatially...
Abstract To investigate the class‐dependent properties of anti‐viral IgM antibodies, we use membrane antigen capture activated cell sorting to isolate spike‐protein‐specific B cells from donors recently infected with SARS‐CoV‐2, allowing production recombinant antibodies. We 20, antibodies classes IgM, IgG, and IgA, none which shows any antigen‐independent binding human cells. Two class mediate virus neutralization at picomolar concentrations, but this potency is lost following artificial...
Affinity data, such as dissociation constants (KD ) or inhibitory concentrations (IC50 ), are widely used in drug discovery. However, these parameters describe an equilibrium state, which is often not established vivo due to pharmacokinetic effects and they therefore necessarily sufficient for evaluating efficacy. More accurate indicators pharmacological activity the kinetics of binding processes, shed light on rate formation protein-ligand complexes their half-life. Nonetheless, although...
PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other agents, orally bioavailable and not a P-glycoprotein substrate. So as to characterize position the molecule for optimal clinical development, interactions of with tubulin using crystallography, its spectrum preclinical
Abstract In this research article, we report on the strengthening of a non‐classical hydrogen bond (C−H⋅⋅⋅O) by introducing electron withdrawing groups at carbon atom. The approach is demonstrated example derivatives physiological E‐selectin ligand sialyl Lewis x ( 1 , sLe ). Its affinity mainly due to beneficial entropy term, which predominantly caused pre‐organization in its binding conformation. We have shown, that among elements responsible for pre‐organization, stabilization between...
Abstract Tubulin plays essential roles in vital cellular activities and is the target of a wide range proteins ligands. Here, using combined computational crystallographic fragment screening approach, we addressed question how many binding sites exist tubulin. We identified 27 distinct sites, which 11 have not been described previously, analyzed their relationship to known tubulin–protein tubulin–ligand interactions. further observed an intricate pocket communication network 56 chemically...
<title>Abstract</title> Molecular photoswitches are versatile natural or synthetic molecules that undergo reversible conformational changes in response to light. In chemistry azobenzenes act as ubiquitous photoswitches<sup>1</sup> with applications ranging from opto-electronics<sup>2</sup>, over molecular machines<sup>3</sup> photopharmacology<sup>4</sup>. Their isomerization mechanism defines their properties and yet is controversially debated, the underlying ultrafast photochemistry...
Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized tubulin-binding activity, mechanism action, and in vivo anti-leukemia efficacy three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target colchicine-binding site tubulin none a substrate ABC transporters. The crystal structure tubulin-bound N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on T7 loop...
Abstract In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells G2/M, induces cell death, synergizes vinblastine. The compound destabilizes microtubules by acting as molecular plug that sterically inhibits curved‐to‐straight conformational switch α‐tubulin...
Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency strengthen establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved be successful, not only with sites, but also that possess a single recognition domain. Herein we present syntheses number ligands...
The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure DDM evaluated activity novel congeners in triple negative breast ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified lactone diene as moieties conferring anticancer activity, thus identifying priorities for structural refinement studies described herein. Congeners possessing monodiene...