Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

Abstract

Ligands that bind to and stabilize guaninequadruplex (G4) structures to regulate DNA replication have therapeutic potential for cancer and neurodegenerative diseases. Because there are several G4 topologies, ligands that bind to their specific types may have the ability to preferentially regulate the replication of only certain genes. Here, we demonstrated that binding ligands stalled the replication of template DNA at G4, depending on different topologies. For example, naphthalene diimide derivatives bound to the G-quartet of G4 with an additional interaction between the ligand and the loop region of a hybrid G4 type from human telomeres, which efficiently repressed the replication of the G4. Thus, these inhibitory effects were not only stability-dependent but also topology-selective based on the manner in which G4 structures interacted with G4 ligands. Our original method, referred to as a quantitative study of topologydependent replication (QSTR), was developed to evaluate correlations between replication rate and G4 stability. QSTR enabled the systematic categorization of ligands based on topology-dependent binding. It also demonstrated accuracy in determining quantitatively how G4 ligands control the intermediate state of replication and the kinetics of G4 unwinding. Hence, the QSTR index would facilitate the design of new drugs capable of controlling the topology-dependent regulation of gene expression.

Modulation of the Conformational Space of SARS‐CoV‐2 RNA Quadruplex RG‐1 by Cellular Components and the Amyloidogenic Peptides α‐Synuclein and hIAPP

“…[ 4 , 5 , 6 , 7 , 8 ] Recently, non‐canonical nucleic acids structures, such as G‐quadruplexes (G4Qs), have also been recognized as promising therapeutic targets. [ 7 , 8 , 9 , 10 , 11 ] The structure of G4Qs is characterized by the stacking of two or more planar arranges of G‐tetrads which are stabilized by lateral Hoogsteen‐type hydrogen bonds and by the coordination of a monovalent cation, such as K + (Figure 1 ). [11] Depending on the orientation of the G‐tetrades, the structure of G4Qs can be parallel (with four G‐tetrades in the same orientation), antiparallel (with two G‐tetrades in opposite orientation with respect to the other two), or hybrid (with one G‐tetrade in opposite orientation with respect to the other three) and further distinguished by their loop position (for example, antiparallel basket or chair conformation as well as different types of hybrid structures).…”

“…G4Qs have therefore received considerable attention over the last twenty years due to their involvement in the regulation of cellular processes including replication, transcription and translation. [ 10 , 11 , 12 , 13 , 14 , 15 ] Dysregulation of G4Q formation and their binding proteins, which assist them in regulating the equilibrium between their structured and unstructured/unfolded forms, due to mutations or through the alteration of their stability by environmental factors (for example, by changes in intracellular solution conditions or by G4Q‐stabilization induced by a ligand), have been found to contribute to many human pathologies, including neurodegenerative diseases, cancer, and microbial infections. [ 4 , 5 , 6 , 7 ]…”

Phen‐DC3 Induces Refolding of Human Telomeric DNA into a Chair‐Type Antiparallel G‐Quadruplex through Ligand Intercalation

“…[17,18] However, G4 polymorphism makes it challenging to understand and design specific recognition of particular structure(s) by ligands. [25][26][27] The polymorphism arises from differences in strand stoichiometry, position and conformation of the loops connecting Gs and mutual orientations of G-tracts in the core of the structure. [28] The archetypal polymorphic sequence is the human telomeric repeat sequence (TTAGGG) n , for which diverse (parallel, antiparallel and hybrid) intramolecular folding topologies have been identified (Figure 1).…”

Binding Properties of RNA Quadruplex of SARS-CoV-2 to Berberine Compared to Telomeric DNA Quadruplex

“…So far, efficient and safe antiviral agent have not been developed [ 4 , 5 , 6 , 7 ]. In recent years, non-canonical nucleic acids structures, such as G-quadruplexes, have been spotlighted as promising therapeutic targets [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. G-quadruplexes (G4Qs) are common in guanine-rich regions and are characterized by the stacking of two or more planar arrangements of four guanines (tetrads), which are stabilized by the formation of Hoogsten-type hydrogen bonds and by the interaction with monovalent cations (Na + , K + ) placed in their central canal ( Figure 1 ).…”

“…G-quadruplexes (G4Qs) are common in guanine-rich regions and are characterized by the stacking of two or more planar arrangements of four guanines (tetrads), which are stabilized by the formation of Hoogsten-type hydrogen bonds and by the interaction with monovalent cations (Na + , K + ) placed in their central canal ( Figure 1 ). G4Qs have received particular attention due to their involvement in the control of gene expression [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Dysregulation of G4Q formation and their binding proteins, which assist them in regulating the equilibrium between their structured and unstructured forms, due to mutations or via the alteration of their stability by environmental factors (e.g., by G4Q-stabilization induced by a polypeptide or small-molecule ligand), have been found to contribute to many human pathologies, including neurodegenerative diseases, cancer, and microbial infections [ 17 ].…”