The coronavirus disease 2019 (COVID-19) pandemic has been ongoing since 2019, and it has tremendously affected the global healthcare system and economy. This pandemic has been caused by the rapid outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has claimed more than 6.27 million lives worldwide.
Scientists have characterized SARS-CoV-2 as a positive sense mRNA virus that belongs to the family Coronaviridae and genus Betacoronavirus. Two other coronaviruses that have caused an epidemic in the last two decades are severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).
The continual mutation of SARS-CoV-2 genomes has challenged the efficacy of the available COVID-19 vaccines. Scientists have reported the emergence of several variants and categorized them as variants of concern (VOC) and variants of interest (VOI). Among the VOCs, the Omicron (B.1.1.529) variant has presently become the dominantly circulating strain in many parts of the world. This variant is highly transmissible and has the capacity to evade the immune responses elicited by COVID-19 vaccination and natural infection. The reduced efficacy of the available vaccines against VOCs has led to an urgent need to create orally available anti-coronaviral agents to protect individuals from the virus.
Researchers stated that RNA-dependent RNA polymerase (RdRp) is a key component of viral replication machinery and has been considered an important target for developing anti-SARS-CoV-2 drugs. Several nucleoside and nucleotide analogs, for example, remdesivir, favipiravir, AT-527, and molnupiravir, have been repurposed for the treatment of COVID-19 infection.
Even though remdesivir has been reported to be effective against SARS-CoV-2 infection, it has to be administered via intravenous route, which limits its usage in clinical settings. Several studies have revealed that the parent nucleoside of remdesivir, GS-441524, is a 1’-cyano-substituted adenosine analog that possesses wide-ranging antiviral activities across multiple viral families.
Hence, scientists believe that GS-441524 could be used as a lead compound to design anti-SARS-CoV-2 drugs for oral delivery. Recent studies have reported that two derivatives of GS-441524, namely GS-621763 and VV116, exhibited the potential for oral administration for SARS-CoV-2 treatment.
A new study
A new study published in Science Translational Medicine has revealed that ATV006, which is a 5′-hydroxyl-isobutyryl prodrug, possesses extraordinary oral pharmaco-kinetic (PK) profiles in rats and cynomolgus monkeys and exhibited significant antiviral activity against ancestral SARS-COV-2 strain as well as VOCs.
In this study, scientists designed and synthesized a series of derivatives of GS-441524 by incorporating short-chain fatty acids (SCFAs) or amino acid modification. These modifications helped mask the polar hydroxyl- or amino acid derivatives. Researchers assessed the antiviral activity of these compounds against SARS-CoV-2 ancestral strain and VOCs, such as the Omicron, Beta, and Delta in Vero-E6 and Huh7 cell cultures.
Scientists used three SARS-CoV-2 mouse models in this study, which included mice with adenovirus-delivered hACE2 (Ad5-hACE2), knock-in hACE2 at the mAce2 gene locus (KI-hACE2), and transgenic K18-hACE2. The therapeutic efficacy of ATV006 was assessed based on the weight of the treated/untreated mouse, viral detection via various assays, immunostaining analysis, qRT-PCR, histopathology, and survival analysis.
Researchers stated that among the compounds synthesized, the isobutyryl adenosine analog ATV006 revealed improved oral absorption and could effectively inhibit SARS-CoV-2 replication. Importantly, this drug was found to be effective against two VOCs, namely, the Delta and Omicron variants. Most importantly, compared to remdesivir, scientists stated that ATV006 is structurally simpler and can be synthesized easily by a three-step transformation process with GS-441524 as the starting compound. Hence, it will not only accelerate production time but also cut down the cost of production.
Researchers stated that ATV006 and remdesivir share a similar mechanism of inhibiting the viral polymerase, i.e., by targeting RdRp. Several studies have reported that GS-441524 is effective against many viruses belonging to the family Coronaviridae, Filoviridae, and Paramyxoviridae, which indicates a wide-ranging application of ATV006.
In this study, researchers tested the efficacy of ATV006 against the SARS-CoV-2 virus by three different mouse modes tested by four independent research groups, and the results of all the mouse models were consistent and showed robust antiviral activity.
Among the three mouse models, the highly sensitive K18-hACE2 mice were used for prophylactic and therapeutic studies. In the prophylactic model, scientists revealed that ATV006 could effectively prevent the death of K18-hACE2 mice infected with the SARS-CoV-2 Delta variant. This is because the drug compound could effectively inhibit SARS-CoV-2 replication at the early phase of infection.
A key limitation of the study is that it includes SARS-CoV-2 mouse models that cannot fully mimic the disease pathogenesis related to SARS-CoV-2 infection in humans. Hence, more studies must be conducted to determine the antiviral activity of ATV006 in humans. In the future, the oral bioavailability of ATV006 must be determined in humans along with its dosage scheme.