H2020Индивидуална стипендия2018–2020

CaLecLig · Calcium-dependent Lectins in Human Pathogenic Infections: From Atomistic Understanding to Ligand Design

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-06-01 → 2020-05-31
Финансиране от ЕС: 185 076 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Лектините са протеини, които разпознават захари и влияят върху инфекциите, като например при кистичната фиброза. Разбирането на техните молекулярни връзки помага за създаването на нови лекарства.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Calcium-dependent Lectins in Human Pathogenic Infections: From Atomistic Understanding to Ligand Design

Summary Human health and disease are defined by balance between pathogen attack and immunologic defense. In these processes, specific binding among cells mediated by recognition of carbohydrates by protein receptors, lectins, is crucial. Molecular details can be harnessed to design glycomimetic drugs, e.g. Tamiflu. This is challenging due to the flexibility of lectin–carbohydrate complexes. We utilized molecular modeling to interpret experimental data. The three studied lectins are important for infections in cystic fibrosis patients (LecA/B) and in human immune response to infection (DC-SIGN). Their ligands are bound via calcium ions, whose theoretical description is difficult. We have developed new protocols which can potentially become a fundamental toolbox in glycomimetic drug design. Objectives The goal is to develop a workflow for predicting dynamics of three lectins in complex with ligands. Such protocols are transferable to other systems and thus foster rational design of new potent specific compounds with high pharmaceutical potential. The specific objectives include creating, testing and validating ligand/calcium parametrisations and developing protocols for accurate binding mode predictions. Conclusions We tested and developed protocols for calculations of lectin/calcium/ligand complexes which are transferable to other biomolecular complexes and thus potentially useful in developing new drugs. Importance for European Society The benefits of this Action for the European Research Area are not only in the high-profile scientific results obtained solely at European scientific institutions and novel computational methodologies. New interdisciplinary collaborations and scientific links across Europe were formed and together with mobility of the European researchers, knowledge and skills increased. Further, presentations of the results at international conferences enhanced the attractiveness of Europe as a scientific career location. Due to the dissemination of the results and outreach activities of the Experienced Researcher, the knowledge about this Europe-based research was made known not only to scientists in this and related fields but also to pharmaceutical industry and general public. Along all these lines, the competitiveness of European Research Area was hugely increased.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Lectins are proteins that bind saccharides, thus mediating cell-cell and cell-pathogen adhesion. They are therefore implicated in many devastating diseases (cancer, diabetes). The pharmaceutical industry had to leverage the remarkable progress in modern methodologies to cope with the enormous challenges of targeting lectins (flexible interactions involving calcium, multivalent ligands/multimeric receptors), producing a dozen of successful glycomimetic drugs (e.g. Tamiflu). To develop workflows comparable to traditional drug/target complexes, however, deep knowledge of lectin/ligand interactions must be gained. This project aims to fill this gap by determining the properties of Ca2+-dependent lectins, LecA/B and DC-SIGN, implicated in bacterial infections of cystic fibrosis patients and viral infections (HIV-1, Ebola), respectively. We will establish the microscopic view of Ca2+ binding to these lectins using advanced molecular dynamics (MD), verified by quantum mechanical (QM) calculations, isothermal titration calorimetry (ITC) and neutron crystallography. Then, we will work out protocol for predicting lectin-ligand binding modes and affinities using free-energy simulations, verified by NMR data. Finally, we will create a dynamic model of DC-SIGN tetramer by fitting to SAXS envelope and interpret multivalent binding types. The proposed project is novel and multidisciplinary. The applicant will acquire training in advanced experimental and computational techniques, which will re-enforce his career prospects in research and teaching. Conversely, he will transfer his knowledge of QM calculations to the host and partner institutions. This unique complementarity of competences will bring fundamental and practical understanding of lectin-ligand binding which will advance glycoscience research and industry. Future design of new patentable glycomimetics will impact Europe’s economy and society.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция