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455 Publications visible to you, out of a total of 455
Enhanced sampling simulations and machine learning to address infectious diseases

Abstract

Not specified

Author: Matheus Ferraz

Date Published: 2023

Publication Type: Doctoral Thesis

Computational Investigation of the Structure Kinetics Relationship of Small-Molecule Compounds Binding the Histamine-1-Receptor

Abstract

Not specified

Author: Melanie Kaeser

Date Published: 9th Dec 2022

Publication Type: Master's Thesis

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth.

Abstract (Expand)

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression … of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.

Authors: L. Costantino, S. Ferrari, M. Santucci, O. M. H. Salo-Ahen, E. Carosati, S. Franchini, A. Lauriola, C. Pozzi, M. Trande, G. Gozzi, P. Saxena, G. Cannazza, L. Losi, D. Cardinale, A. Venturelli, A. Quotadamo, P. Linciano, L. Tagliazucchi, M. G. Moschella, R. Guerrini, S. Pacifico, R. Luciani, F. Genovese, S. Henrich, S. Alboni, N. Santarem, A. da Silva Cordeiro, E. Giovannetti, G. J. Peters, P. Pinton, A. Rimessi, G. Cruciani, R. M. Stroud, R. C. Wade, S. Mangani, G. Marverti, D. D'Arca, G. Ponterini, M. P. Costi

Date Published: 7th Dec 2022

Publication Type: Journal

Identification of antiparasitic drug targets using a multi-omics workflow in the acanthocephalan model

Abstract (Expand)

Abstract Background With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated …er, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans ( Pomphorhynchus laevis, Neoechinorhynchus agilis , Neoechinorhynchus buttnerae ) from four fish species (common barbel, European eel, thinlip mullet, tambaqui). Results The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel. Conclusions The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URL tinyurl.com/yx72rda7 .

Authors: Hanno Schmidt, Katharina Mauer, Manuel Glaser, Bahram Sayyaf Dezfuli, Sören Lukas Hellmann, Ana Lúcia Silva Gomes, Falk Butter, Rebecca C. Wade, Thomas Hankeln, Holger Herlyn

Date Published: 1st Dec 2022

Publication Type: Journal

MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I

Abstract

Not specified

Authors: Marcus Fabiano de Almeida Mendes, Marcelo de Souza Bragatte, Priscila Vianna, Martiela Vaz de Freitas, Ina Pöhner, Stefan Richter, Rebecca C. Wade, Francisco Mauro Salzano, Gustavo Fioravanti Vieira

Date Published: 28th Oct 2022

Publication Type: Journal

Diffusion of small molecule drugs is affected by surface interactions and crowder proteins

Abstract

Not specified

Authors: Debabrata Dey, Ariane Nunes-Alves, Rebecca C. Wade, Gideon Schreiber

Date Published: 1st Oct 2022

Publication Type: Journal

Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway

Abstract

Not specified

Authors: Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade

Date Published: 2nd Sep 2022

Publication Type: Journal

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