Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries

Jiang, Qianqian; Sicking, Wilhelm; Ehlers, Martin; Schmuck, Carsten

doi:10.1039/c4sc02943g

Cited by 29 publications

(23 citation statements)

References 73 publications

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“…On the basis of these promising computational results, we synthesised ligand 1 by using our previously established procedures for related compounds . Following the six‐step route to the tert ‐butoxycarbonyl (Boc)‐protected GCP, we used (benzotriazol‐1‐yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)‐mediated peptide coupling with H‐Lys(Boc)‐OMe to obtain the protected version of 1 , which was then deprotected to obtain the final compound (details can be found in the Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Rational Design, Binding Studies, and Crystal‐Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14‐3‐3ζ Adapter Protein

et al. 2018

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14-3-3 Proteins play a central role in signalling pathways in cells: they interact as gatekeeper proteins with a huge number of binding partners. Their function as hub for intracellular communication can explain why these adapter proteins are associated with a wide range of diseases. How they control the various cellular mechanisms is still unclear, but it is assumed that the dimeric nature of the 14-3-3 proteins plays a key role in their activity. Here, we present, to the best of our knowledge, the first example of a small molecule binding to the 14-3-3ζ dimerisation interface. This compound was designed by rational in silico optimisation of a peptidic ligand identified from biochemical screening of a peptidic library, and the binding was characterised by UV/Vis spectroscopy, microscale thermophoresis, multiscale simulations, and X-ray crystallography.

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Section: Resultsmentioning

confidence: 99%

Rational Design, Binding Studies, and Crystal‐Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14‐3‐3ζ Adapter Protein

et al. 2018

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“…Inhibition of PPIs is considered challenging in view of the fact that such interactions involve extended and less well‐defined surfaces than the “lock‐and‐key”‐like interfaces that have historically proven to be tractable targets for drug‐discovery 4. Several supramolecular scaffolds have been explored as templates upon which to elaborate ligands for selective and high affinity protein‐surface binding,5 including: porphyrins,6, 7, 8, 9 calixarenes,9, 10, 11, 12, 13 cucurbiturils,14, 15 molecular clips,16, 17 ruthenium(II) tris‐chelates18, 19, 20, 21, 22, 23 and other ligands 24, 25, 26, 27. These function by projecting multiple binding groups from the scaffold so as to cover a large surface area and make multivalent contacts with the protein surface 5.…”

Section: Introductionmentioning

confidence: 99%

Generation of Dynamic Combinatorial Libraries Using Hydrazone‐Functionalized Surface Mimetics

Hewitt

Wilson

2018

Eur J Org Chem

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Dynamic combinatorial chemistry (DCC) represents an approach, whereby traditional supramolecular scaffolds used for protein surface recognition might be exploited to achieve selective high affinity target recognition. Synthesis, in situ screening and amplification under selection pressure allows the generation of ligands, which bear different moieties capable of making multivalent non‐covalent interactions with target proteins. Generic tetracarboxyphenyl porphyrin scaffolds bearing four hydrazide moieties have been used to form dynamic combinatorial libraries (DCLs) using aniline‐catalyzed reversible hydrazone exchange reactions, in 10 % DMSO, 5 mm NH4OAc, at pH 6.75. High resolution mass spectrometry (HRMS) was used to monitor library composition and establish conditions under which equilibria were established.

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“…Thus, the surface performances such as switchable biofunction, tunable wettability, and reversible cell adhesion could be dramatically altered. 19,20 Using the hydrazone-based DCBs, Mahon et al 21 have established polymer-scaffolded dynamic combinatorial libraries in aqueous solution by reversible conjugation of different acylhydrazide residues onto aldehydefunctionalized dimethylacrylamide-based polymer scaffolds. Moreover, the Diels-Alder bond based dynamic switchable surface system usually requires multiple synthesis steps, which are not efficient enough.…”

Section: Introductionmentioning

confidence: 99%

Switching biological functionalities of biointerfaces via dynamic covalent bonds

Deng

Cheng

et al. 2016

J. Mater. Chem. B

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The development of biointerfaces with switchable properties is of growing interest for fabricating advanced biomaterials since the adjustment of surface properties can be made on demand. Herein, we report a highly versatile approach for the preparation of a switchable biointerface through a dynamic covalent bond (DCB). The switchability can be achieved via the reversible attaching/detaching of aldehyde end-functionalized biomacromolecules onto/from an acylhydrazide anchored substrate surface. By applying the DCB protocol, three types of well-designed aldehyde end-functionalized biomacromolecules including aldehyde-poly(styrenesulfonate)-co-poly(ethylene glycol)methyl ether methacrylate (Ald-PSP, blood compatible), aldehyde-poly([2-(meth acryloyloxy)ethyl]trimethylammonium chloride) (Ald-PMT, antibacterial), and aldehyde-poly([2-(meth acryloyloxy)ethyl]trimethylammonium chloride-co-poly(ethylene glycol)methyl ether methacrylate) (Ald-PMP, combined antifouling and antibacterial) could be reversibly and alterably immobilized on the substrate surface by switching the pH conditions. As a result, we succeeded in altering the biointerface performances; excellent blood compatibility, antibacterial ability, or combined antifouling and antibacterial capabilities could be alterably achieved on the biointerface, which made the obtained material interfaces more adaptable and capable of satisfying different biofunctional requirements. Moreover, many other properties with specific biofunctions of interests can also be achieved via designing specific aldehyde-terminated molecules.

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Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries

Cited by 29 publications

References 73 publications

Rational Design, Binding Studies, and Crystal‐Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14‐3‐3ζ Adapter Protein

Rational Design, Binding Studies, and Crystal‐Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14‐3‐3ζ Adapter Protein

Generation of Dynamic Combinatorial Libraries Using Hydrazone‐Functionalized Surface Mimetics

Switching biological functionalities of biointerfaces via dynamic covalent bonds

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