HEИндивидуална стипендия2022–2024

QDHassay · In vitro and In-cell characterization of Quadruplex-duplex hybrids: conformation, folding, and recognition by drug-like ligand molecule

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

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 166 279 €
Участници: 2
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Хибридните структури от ДНК и РНК, съчетаващи двойни спирали и G-квадруплекси, се анализират чрез взаимодействието им с малки молекули. Това помага за разработването на по-прецизни лекарства и нанотехнологии, като се разбере как тези структури се държат в живите клетки.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

In vitro and In-cell characterization of Quadruplex-duplex hybrids: conformation, folding, and recognition by drug-like ligand molecule

The formation of secondary structures in nucleic acids affects regulatory processes and diseases. In addition to the Watson-Crick duplex, guanine-rich sequences can form G-quadruplexes (G4), important targets in structural biology. The G-quadruplex-duplex hybrid (QDH) combines G4 and duplex stem-loop structures, stabilized by Hoogsteen and Watson-Crick hydrogen bonding. Genomic studies indicate over 80,000 such sequences in the human genome, highlighting their roles in biological processes. Therefore, the design of high-affinity and selective ligands targeting quadruplex-duplex junctions is of immense importance. There is insufficient structural information on how G4-specific ligands regulate different quadruplex-duplex hybrid scaffolds. A significant limitation is the lack of structural information regarding how ligands with similar pharmacophore scaffolds interact across different conformations with similar sequences. Addressing this knowledge gap is vital for developing small-molecule ligands that modulate quadruplex-duplex hybrid conformations in drug design and nanotechnology. It is to be noted that although in vitro (as well as in silico) approaches provide qualitative and quantitative insights into ligand binding archetypes, these conditions may not precisely reflect their efficacy in vivo, where alternative targets (proteins, genomic DNA, RNA, etc.) and various environmental factors can perturb the formation, folding, and stability of complexes. Consequently, monitoring quadruplex-duplex hybrid–ligand interactions within a cellular context is intriguing because of the lack of appropriate biophysical tools.

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

Цел на проекта

Nucleic acids are intrinsically polymorphic. Apart from the Watson-crick duplex, guanine-rich sequences can form G-quadruplex (G4) structures, which have become attractive targets for small molecule ligands. It is now proven that G-quadruplexes can form in cells. Today most biophysical and structural/ligand binding studies are carried out in dilute aqueous solutions and the presence of artificial crowding agents/cosolvents. Still, recent works suggest that the folding of G4s may differ in the cellular milieu context due to the agents' limitations. Thus there is an immense need for in-cell-based structural biology approaches. In the proposal, I aim to address critical milestones leading to the bioactive conformation inside the cell and the development of effective/specific G4 targeting drugs using an essential sub-class of G4 structures as a paradigm, namely quadruplex−duplex hybrids (QDH-hereafter). We will focus on low- and high-resolution spectroscopic approaches and mass spectrometry-based ligand screening assays characterizing ligand-QDH interaction. On the methodological part, we will develop in-cell NMR in ""native"" conditions (starting from unfolded conformation: denovo folding) and propose a ligand screening assay inside the cellular system. Our project will contribute to unveil fundamental principles of nucleic acid folding. It will also foster collaboration between two European institutes specialized in complementary biophysical and structural approaches to study biomolecular folding. In a nutshell, the Maria Skłodowska Curie fellowship will flourish my scientific excellence and the resilience needed for my original ideas to become a reality and communication and public engagement skills across cultures and disciplines.""

Оригинален текст от CORDIS (на английски).

Участници

Masarykova univerzita · BrnoКоординаторЧехия
JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN · Frankfurt Am MainГермания