Are G-quadruplexes a winning strategy for anti-Covid drugs?

Chinese scientists have identified a novel way of inhibiting the SARS-Cov-2 virus – potentially paving the way for an effective drug against Covid-19.

A consortium of four Chinese institutions says that its targeting of G-quadruplexes (G4s) in the SARS-Cov-2 virus provides an “alternative strategy” for combating the disease.

To date, much anti-Covid viral drug development has focused on RNA polymerases and proteases, as well as viral structure proteins and host proteins. However, interest has also grown recently in targeting noncanonical G4s to inhibit a number of problematic viruses – including Hepatitis C, Ebola, and Zika.

G4s are stacked guanine tetrad, secondary nucleic acid structures that can form within the DNA or RNA of guanine-rich strands. They have been found in the genome of humans, yeasts, bacteria and viruses, and are involved in regulating various biological processes - including transcription, translation and genome stability.

The focus is now on whether G4 can form in the context of SARS-CoV-2 infection, and the formed G4 can act as a therapeutic target for Covid-19 – a field of research that is gathering increasing attention.

Encouragingly, the Chinese study not only identified “several highly conservative and stable G4s in SARS-Cov-2", but also confirmed that RNA G4s were formed in the context of infection by the virus. In addition, the consortium discovered that the G4-specific ligand TMPyP4 was more effective against SARS-Cov-2 infection than remdesivir, both in vitro and in vivo.

Writing in Cell Discovery, the group announced that it had “confirmed the formation of RNA G4s in the context of SARS-CoV-2 infection and clarified their dual-function of inhibiting viral replication and translation processes.

“Furthermore, the inhibitory effects of SARS-CoV-2 G4s can be enhanced by G4- specific ligands 5,10,15,20-tetrakis-(Nmethyl-4-pyridyl) porphine (TMPyP4).

“Different from the existing anti-SARS-CoV-2 therapeutic strategies, our finding provides another alternative therapeutic strategy for SARS-CoV-2 infection focusing on targeting functional secondary structures within SARS-CoV-2 genome.”

There are still limitations in this study, however. One major concern is that, since cellular G4s broadly influence many biological processes, the off-target of TMPyP4 may cause side effects.

Nevertheless, the Chinese group reported some promising outcomes from its murine and cell studies, stating: “TMPyP4 has shown effective antiviral activity in Vero E6 cells, Syrian hamster and human angiotensin-converting enzyme 2 (hACE2) transgenic mouse model of SARS-CoV-2 infection with no observable toxicity.

Although the potential human side effects of TMPyP4 are as yet unknown, the researchers state in Cell Discovery that the porphyrin compound “has the potential to be a short-term treatment of COVID-19 for 1–2 weeks, as COVID-19 is an acute disease.”

They call for it to be “accelerated into clinical trials for COVID-19” - and for more investigation of compounds that specifically target viral, but not host, G4s.

The group also noted that “although we have demonstrated the regulatory effects of G4s on the replication and translation processes of SARS-CoV-2, the roles of G4s in SARS-CoV-2 life cycle are not fully elucidated.”

It added that it was mindful of how the Covid-19 pandemic had “continued to affect millions of lives worldwide”, and that developing novel therapeutic strategies was an urgent consideration - particularly given the threat posed to vaccines by new variants.