New quinoline-based antiviral shows strong promise against SARS-CoV-2

New quinoline-based antiviral shows strong promise against SARS-CoV-2

A study found that Jun13296, a new PLPRO inhibitor, shows potent antiviral and anti-inflammatory effects in vivo, offering hope for future Covid-19 therapies beyond paxlovid.

A recently published study inNature communicationDiscusses the development of a quinoline-based drug candidate with inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease (PLPRO).

The development of antiviral novels against SARS-CoV-2

During the coronavirus disease 2019 (Covid-19) pandemic, researchers around the world investigated the potential effectiveness of existing antiviral and anti-inflammatory drugs against SARS-COV-2 to reduce disease severity and mortality. At the same time, extensive efforts have been made to develop novel broad-spectrum oral antivirals to prevent and treat future pandemics caused by similar pathogens.

Broad-spectrum antivirals must target antigens such as polymerases and proteases, which are conserved across a wide range of viral pathogens. For example, remdesivir and molnupiravir exhibit conserved activity against the hepatitis C virus, filoviruses such as Ebola virus, coronaviruses such as SARS-CoV and SARS-CoV-2, pneumoviruses such as respiratory syncytial and paramyxovirus, measurements and Hendra viruses and Hendra virus.

In the early drug development stages of the Covid-19 pandemic, the SARS-COV-2 cysteine ​​protease Mpro was identified as a potential target for novel therapeutics. Using high-throughput screening (HTS) methods coupled with drug design techniques, MPRO inhibitors such as nirmatrelvir have been developed.

Paxlovid, a combination of nirmatrelvir with the metabolic enhancer ritonavir, is currently approved by the US Food and Drug Administration (FDA) for the treatment of mild to moderate COVID-19. Similarly, ensitrelvir, a noncovalent MPRO inhibitor, received approval in Japan and Singapore.

Despite these advances, other therapeutic targets remain to be identified due to the emergence of SARS-CoV-2 strains with novel MPRO mutations. For example, P132H is a commonly observed MPRO mutation that has not yet developed resistance to nirmatrelvir.

Several studies have reported the presence of triple MPRO mutants such as L50F/E166A/L167F, which are reproductively fit but exhibit strong drug resistance. Likewise, a Covid-19 patient with weakened immunity was found to harbor the NSP5-L50F/E166V mutant after prolonged paxlovid treatment.

Papain-like protease inhibitors

The SARS-COV-2 PLPRO is a cysteine ​​protease required for virus replication and suppression of host immune responses. To date, experimental PLPRO inhibitors have shown limited performanceIn vivoEffectiveness.

The authors of the current study previously developed a covalent PLPRO inhibitor jun11313 that bound to the binding site of Val70ub. To facilitate further aromatic substitutions in the ring while targeting the same site, the naphthalene-based structure was replaced with quinoline conjugated with a linker amino acid moiety to improve its binding affinity.

Further optimization and testing led to the identification of a noncovalent biarylphenyl PLPRO inhibitor JUN12682. Afterwards, Jun12682 was designed to be bound to both the blocking loop region 2 (BL2) and Val70UB.

A number of quinoline analogs have been confirmed to bind to the Val70UB site via their 2-aryl substituents using X-ray crystallography. However, Jun12665 ​​showed a flipped orientation, causing its 2-pyrazolyl group to fit into the BL2 groove.

Jun13296 – promising drug candidate

Jun13296 was identified as the most potent compound with 10-fold activity compared to Jun12682 against SARS-CoV-2 and PLPRO.

Jun13296 has a biphasic pattern of plasma release, with two peaks observed at two and eight hours after oral administration and two and four hours after intravenous administration. After oral dosing, levels of 13296 Jun13296 remained higher than the effective antiviral concentration for more than eight hours.

In vivoStudies confirmed the greater antiviral efficacy of Jun13296 compared to Jun12682. Jun13296 also reduced the activity of inflammatory cytokines such as interleukin 6 (IL-6) and interferon γ (IFN-γ), which may contribute to their superior survival advantage despite active viral replication at lower doses.

The anti-inflammatory activity of Jun13296 may be the result of its inhibition of other enzymatic processes associated with PLPRO such as deubiquitinase and deigylase. However, this hypothesis requires further investigation.

Due to its different mechanism of action, Jun13296 remains effective against SARS-COV-2 variants that have developed resistance to nirmatrelvir, as well as the recent SARS-COV-2 Omicron variants. Jun13296 was also effective again, a triple mutant SARS-CoV-2 variant isolated from an immunocompromised patient on prolonged paxlovid treatment as well as the quadruple mutant selected under viral passage under drug exposure conditions.

In mice with SARS-COV-2 infection, Jun13296 administration increased survival, reduced weight loss, reduced viral load in the lungs, and prevented pneumonia and tissue damage.

These results highlight the potential of quinoline PLPRO inhibitors as promising oral SARS-CoV-2 antiviral candidates. “

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