0000000000014856
AUTHOR
Patrick Johe
showing 7 related works from this author
Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors.
2016
We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach…
Graphical Workflow System for Modification Calling by Machine Learning of Reverse Transcription Signatures
2019
Modification mapping from cDNA data has become a tremendously important approach in epitranscriptomics. So-called reverse transcription signatures in cDNA contain information on the position and nature of their causative RNA modifications. Data mining of, e.g. Illumina-based high-throughput sequencing data, is therefore fast growing in importance, and the field is still lacking effective tools. Here we present a versatile user-friendly graphical workflow system for modification calling based on machine learning. The workflow commences with a principal module for trimming, mapping, and postprocessing. The latter includes a quantification of mismatch and arrest rates with single-nucleotide re…
Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain.
2016
Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors. We thank Fundacion Española para la Ciencia y la Tecnología (Fecyt) and Generalitat Valenciana (AICO/2016/32) for financial support. T S. and B.E. thank the DFG (Deutsche Forschungsgemeinschaft) in the framework of the SFB630 for financial support. We thank Universitat Jaume I for technical suppport and funding. U…
One-pot synthesis of PbS NP/sulfur-oleylamine copolymer nanocomposites via the copolymerization of elemental sulfur with oleylamine
2014
A novel synthetic and processing strategy for converting elemental sulfur into polymeric and nanocomposite materials is reported. We describe a facile one-pot reaction using elemental sulfur and oleylamine as comonomers to prepare high sulfur content copolymers and lead sulfide nanoparticle (PbS NP) nanocomposites. This process enables the preparation of solution processable copolymers and nanocomposites, where the loading and dispersion of PbS NP inclusions could be precisely controlled. We demonstrate the dual roles of oleylamine with sulfur for both the copolymerization of sulfur copolymers as well as the in situ synthesis of PbS NPs in a one-pot fashion.
Warhead Reactivity Limits the Speed of Inhibition of the Cysteine Protease Rhodesain.
2021
Viral and parasitic pathogens rely critically on cysteine proteases for host invasion, replication, and infectivity. Their inhibition by synthetic inhibitors, such as vinyl sulfone compounds, has emerged as a promising treatment strategy. However, the individual reaction steps of protease inhibition are not fully understood. Using the trypanosomal cysteine protease rhodesain as a medically relevant target, we design photoinduced electron transfer (PET) fluorescence probes to detect kinetics of binding of reversible and irreversible vinyl sulfones directly in solution. Intriguingly, the irreversible inhibitor, apart from its unlimited residence time in the enzyme, reacts 5 times faster than …
Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure–Activity Rela…
2021
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorabl…
Structure, interdomain dynamics, and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes
2021
AbstractRhodesain is the lysosomal cathepsin L-like cysteine protease ofT. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression ofT. brucei rhodesiensepro-rhodesain inE. coliand determined its crystal structure. The trypanosomal pr…