RNA G-quadruplex formed in SARS-CoV-2 used for COVID-19 treatment in animal models

Abstract

The ongoing COVID-19 pandemic has continued to affect millions of lives worldwide, leading to the urgent need for novel therapeutic strategies. G-quadruplexes (G4s) have been demonstrated to regulate life cycle of multiple viruses. Here, we identify several highly conservative and stable G4s in SARS-CoV-2 and clarify their dual-function of inhibition of the viral replication and translation processes. Furthermore, the cationic porphyrin compound 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine (TMPyP4) targeting SARS-CoV-2 G4s shows excellent antiviral activity, while its N-methyl-2-pyridyl positional isomer TMPyP2 with low affinity for G4 has no effects on SARS-CoV-2 infection, suggesting that the antiviral activity of TMPyP4 attributes to targeting SARS-CoV-2 G4s. In the Syrian hamster and transgenic mouse models of SARS-CoV-2 infection, administration of TMPyP4 at nontoxic doses significantly suppresses SARS-CoV-2 infection, resulting in reduced viral loads and lung lesions. Worth to note, the anti-COVID-19 activity of TMPyP4 is more potent than remdesivir evidenced by both in vitro and in vivo studies. Our findings highlight SARS-CoV-2 G4s as a novel druggable target and the compelling potential of TMPyP4 for COVID-19 therapy. Different from the existing anti-SARS-CoV-2 therapeutic strategies, our work provides another alternative therapeutic tactic for SARS-CoV-2 infection focusing on targeting the secondary structures within SARS-CoV-2 genome, and would open a new avenue for design and synthesis of drug candidates with high selectivity toward the new targets.

RNA G-quadruplex forming regions from SARS-2, SARS-1 and MERS coronoviruses

“…More recently, TMPyP4 G4-ligands, already known for its antiviral activities against HIV-1, also exhibited antiviral activity against SARS-CoV-2. Remarkably, in Syrian hamster and transgenic mouse models of SARS-CoV-2 infection, administration of TMPyP4 resulted in a significant reduction in viral loads and lung injury ( Qin et al, 2022 ). In the same study, the activity of TMPyP4 proved to be significantly stronger than that of remdesivir.…”

Drugs for COVID-19: An Update

“…Thus, this drug may represent a safe alternative to remdesivir and dexamethasone with both antiviral and anti-inflammatory properties [ 97 ]. Interestingly, G-quadruplexes specific ligands, namely 5,10,15,20-tetrakis-( N -methyl-4-pyridyl)porphine (TMPyP4), showed better antiviral effects than remdesivir on the Vero E6 cells, Syrian hamster and human angiotensin-converting enzyme 2 (hACE2) transgenic mouse model of SARS-CoV-2 infection, with no significant toxicity [ 98 ]. Most importantly, this study provided an alternative strategy for COVID-19 treatment by targeting the secondary genomic structures of SARS-CoV-2, paving the way to the rational design and synthesis of new safer agents.…”

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

“…Through an intensive investigation they found that targeting SARS‐CoV‐2 G4s by PDP and TMPyP4 can significantly inhibit SARS‐CoV‐2 infection in cell‐based assays. [ 52 ] And TMPyP4 showed more potent anti‐SARS‐CoV‐2 activity than PDP and can significantly ameliorate lung damage caused by SARS‐CoV‐2 infection in animal models. [ 52 ] These findings reveal the biological roles of viral RNA G4s in SARS‐CoV‐2 life cycle and highlight the potential of viral RNA G4s as a druggable target for COVID‐19 prevention and treatment.…”

“…On the other hand, due to the availability of a negative control compound TMPyP2, TMPyP4 is widely employed as a tool for studying G4s. [ 7 , 52 , 70 ] TMPyP2 cannot stack on the G4 because of the steric‐hindrance effect, leading to no biological effects. [ 70 ] In viruses, TMPyP4 was also employed to investigate the roles of G4s in the life cycle of various viruses, such as HIV, [ 71 ] Hepatitis C virus (HCV), [ 37 ] Zika virus (ZIKV) [ 38 ] and Ebola virus (EBOV).…”

“…[ 40 ] Importantly, these studies have shown the antiviral activity of TMPyP4 against multiple viruses by targeting G4s in cell‐based assays, including SARS‐CoV‐2. Qu's group [ 52 ] showed that TMPyP4 significantly inhibits SARS‐CoV‐2 infection by targeting SARS‐CoV‐2 G4s in cell‐based assays. Moreover, administration of TMPyP4 effectively suppresses SARS‐CoV‐2 replication and relieves lung lesions in two animal models.…”