Targeting the RNA G-Quadruplex and Protein Interactome for Antiviral Therapy

Abstract

In recent years, G-quadruplexes (G4s), types of noncanonical four-stranded nucleic acid structures, have been identified in many viruses that threaten human health, such as HIV and Epstein–Barr virus. In this context, G4 ligands were designed to target the G4 structures, among which some have shown promising antiviral effects. In this Perspective, we first summarize the diversified roles of RNA G4s in different viruses. Next, we introduce small-molecule ligands developed as G4 modulators and highlight their applications in antiviral studies. In addition to G4s, we comprehensively review the medical intervention of G4-interacting proteins from both the virus (N protein, viral-encoded helicases, severe acute respiratory syndrome-unique domain, and Epstein–Barr nuclear antigen 1) and the host (heterogeneous nuclear ribonucleoproteins, RNA helicases, zinc-finger cellular nucelic acid-binding protein, and nucleolin) by inhibitors as an alternative way to disturb the normal functions of G4s. Finally, we discuss the challenges and opportunities in G4-based antiviral therapy.

Structurally diverse G-quadruplexes as the noncanonical nucleic acid drug target for live cell imaging and antibacterial study

“…46 Nonetheless, since the discovery of biologically relevant G4s in the eukaryotic chromosomal telomeric DNA consisting of the repeated sequence TTAGGG, 47 an unprece-discovery of telomeres and telomerase. 49,50 So far, a lot of structural information about DNA G4s has been reported which shows a great conformational diversity of G4s, which are recognized as potential drug targets against many human diseases, [51][52][53][54][55][56] particularly cancers. [57][58][59][60][61][62][63][64][65][66][67] The relationship between the sequence, structure and stability of G4s, their interactions with small molecules in vitro and in vivo, and insights into the rational design of G4-selective binding ligands have been well documented and intensively reviewed over the decade.…”

Effects of Molecular Crowding on the Structure, Stability, and Interaction with Ligands of G-quadruplexes

“…The PhenDC3 and TMPyP4 (G4 ligands) were found to slow down the replication fork and disrupt the DNA replication of Kaposi sarcoma-associated herpesvirus . The G4’s structure was also identified in the COVID-19 genome and could be an essential drug target for the inhibition of this virus. , …”

“…25 The G4's structure was also identified in the COVID-19 genome and could be an essential drug target for the inhibition of this virus. 26,27 Current studies on G4s have mainly been carried out under diluted solution conditions. However, in reality, the cellular milieu is highly crowded, with a diverse range of molecules, including proteins, polysaccharides, nucleic acids, and other soluble or insoluble substances, occupying a limited amount of available space.…”

“… 25 The G4’s structure was also identified in the COVID-19 genome and could be an essential drug target for the inhibition of this virus. 26 , 27 …”

Unlocking G‐Quadruplexes as Targets and Tools against COVID‐19

“…[ 34 ] Among them, the roles of viral G4s have been widely investigated and the emerging evidence indicated that G4s involved in regulating viral replication, transcription, assembly, virulence, etc ., even G4s can co‐evolve with virus. [ 35 , 36 ] In addition, several G4 ligands have shown potentially interesting antiviral activity in various viruses, including Hepatitis C virus (HCV), [ 37 ] the Zika virus (ZIKV), [ 38 , 39 ] the Ebola virus (EBOV) [ 40 ] and SARS‐CoV‐2.…”