Molnupiravir: a novel efficacious antiviral candidate to COVID-19

An unknown pneumonia-like disease has emerged in Wuhan, China, in late 2019. It is later named as SARS-CoV-2 which cause COVID-19. This virus spreads easily due to high mobilization and its transmission through droplets or aerosol and fomite. The World Health Organization (WHO) then declared this disease as a global outbreak in March 2020. As the world faces the outbreak of SARS-CoV-2, many researchers race to find the most efficacious treatment for COVID-19. Until now, the most common treatments for COVID-19 were only symptomatic such as decongestant, corticosteroid, interleukin inhibitor, and existing antiviral. The researchers then develop a brand new antiviral that works efficiently to inhibit SARS-CoV-2 and might become prophylaxis. This disease is called Molnupiravir or EIDD-2801, a nucleotide analog which inhibits SARS-CoV-2 replication, resulting in damaged mRNA and lethal virions. Molnupiravir works to produce mutagenesis in RNA viruses and prevent the virus from spreading widely throughout the human body. However, this drug is still needed to undergo clinical trial phase three. In this article, we will discuss how Molnupiravir works and its efficacy compared to existing drugs. This review article aims to provide an update about novel efficacious antiviral for COVID-19, Molnupiravir.

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro , with a 50% effective concentration (EC 50 ) of 0.31 µM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log 10 -fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log 10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 – 100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection.

Eicosanoid Metabolomic Profile of Remdesivir Treatment in Rat Plasma by High-Performance Liquid Chromatography Mass Spectrometry

Remdesivir, a nucleotide analog prodrug, has displayed pharmacological activity against SARS-CoV-2. Recently, eicosanoids are widely involved in regulating immunity and inflammation for COVID-19 patients. Rats were intravenously administered remdesivir at a dose of 5 mg/kg, and series of blood samples were collected before and after treatment. Targeted metabolomics regarding the eicosanoid profile were investigated and quantitated simultaneously using the previously reported reliable HPLC-MS/MS method. Additionally, interplay relationship between metabolomics and pharmacokinetic parameters was performed using the Pearson correlation analysis and PLS model. For the longitudinal metabolomics of remdesivir, metabolic profiles of the same rat were comparatively substantial at discrete sampling points. The metabolic fingerprints generated by individual discrepancy of rats were larger than metabolic disturbance caused by remdesivir. As for the transversal metabolomics, the prominent metabolic profile variation was observed between the baseline and treatment status. Except for TXB2, the inflammatory- and immunology-related eicosanoids of resolvin D2, 5-HEPE, 5-HETE, and DHA were significantly disturbed and reduced after single administration of remdesivir (p &lt; 0.05, p &lt; 0.001). Moreover, the metabolite of PGE2 correlated with GS-441524 (active metabolite of remdesivir) concentration and pharmacokinetic parameters of Cmax, AUC0-t, AUC0-infinity, and CL significantly. Eicosanoid metabolic profiles of remdesivir at both longitudinal and transversal levels were first revealed using the robust HPLC-MS/MS method. This initial observational eicosanoid metabolomics may lighten the therapy for fighting COVID-19 and further provide mechanistic insights of SARS-CoV-2 virus infection.

Evaluation of AT-752, a double prodrug of a guanosine nucleotide analog with in vitro and in vivo activity against dengue and other flaviviruses

Every year millions of people worldwide are infected with dengue virus (DENV), with a significant number developing severe life-threatening disease. There are currently no broadly indicated vaccines or therapeutics available for treatment of DENV infection. Here, we show that AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, was a potent inhibitor of DENV serotypes 2 and 3 in vitro , requiring concentrations of 0.48 and 0.77 μM, respectively, to inhibit viral replication by 50% (EC 50 ) in Huh-7 cells. AT-281 was also a potent inhibitor of all other flaviviruses tested with EC 50 values ranging from 0.19 to 1.41 μM. Little to no cytotoxicity was observed for AT-281 at concentrations up to 170 μM. After oral administration of AT-752, substantial levels of the active triphosphate metabolite AT-9010 were formed in vivo in peripheral blood mononuclear cells of mice, rats and monkeys. Furthermore, AT-9010 competed with guanosine triphosphate in RNA template-primer elongation assays with DENV-2 RNA polymerase, which is essential for viral replication, with incorporation of AT-9010 resulting in termination of RNA synthesis. In AG129 mice infected with DENV D2Y98P, treatment with AT-752 significantly reduced viremia and morbidity and increased survival. The demonstrated in vitro and in vivo activity of AT-752 suggest that it is a promising compound for the treatment of dengue virus infection, and is currently under evaluation in clinical studies.

Remdesivir: A Closer Look at Its Effect in COVID-19 Pandemic

<b><i>Background:</i></b> The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every aspect of life. The virus infected over 139 million patients and resulted in over 2.9 million deaths until April 16, 2021. New variants of this virus were identified that spread rapidly worldwide. <b><i>Summary:</i></b> Remdesivir, a prodrug of adenosine nucleotide analog, is an antiviral with a broad spectrum of activity that was tested on SARS and Middle East respiratory syndrome infections. In vitro studies conducted on SARS-CoV-2 revealed that remdesivir inhibited viral replication with high selectivity index in cell cultures. In vivo studies showed that remdesivir reduced viral load in bronchoalveolar lavage fluid and attenuated pulmonary infiltrates in infected animals. Further, remdesivir showed promising results in terms of clinical improvement, shortening the recovery time, mortality rate, and the duration of oxygen need, despite that some clinical trials did not reveal significant effect on remdesivir use. Several studies showed positive results of remdesivir against the new variants. <b><i>Key Messages:</i></b> Remdesivir showed a promising beneficial effect against new variants of SARS-CoV-2, but more clinical evidence is needed to confirm this effect.

Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme

Coronavirus 3′–5′ exoribonuclease (ExoN), residing in the nonstructural protein (nsp) 10-nsp14 complex, boosts replication fidelity by proofreading RNA synthesis and is critical for the virus life cycle. ExoN also recognizes and excises nucleotide analog inhibitors incorporated into the nascent RNA, undermining the effectiveness of nucleotide analog-based antivirals. Here, we present cryo-electron microscopy structures of both wild-type and mutant SARS-CoV-2 nsp10-nsp14 in complex with an RNA substrate bearing a 3′-end mismatch at resolutions ranging from 2.5 Å to 3.9 Å. The structures reveal the molecular determinants of ExoN substrate specificity and give insight into the molecular mechanisms of mismatch correction during coronavirus RNA synthesis. Our findings provide guidance for rational design of improved anti-coronavirus therapies.

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.

Hemorrhagic cystitis: A successful outcome for a challenging complication in stem cell transplant

Hemorrhagic cystitis (HC) secondary to BK polyomavirus (BKPyV) is a frequent complication related to allogenic stem cell transplantation. With an important morbidity and mortality, this disease doesn’t have a stablished standard treatment or prophylaxis strategies. At this moment, the supportive therapies approved to treat included hyperhydration, forced diuresis and transfusion support. Cidofovir is a nucleotide analog of deoxycytidine monophosphate against DNA viruses and it has been described for the treatment of BKPyV-HC, but at this moment, is not a front-line therapy. We report a successful case after the use of Cidofovir without Probenecid. No adverse effect was developed under the treatment, and after 4 weeks of treatment, the patient achieved an excellent response.

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

ABSTRACT The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 μM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.