Oral Methioninase for Covid-19 Methionine-restriction Therapy

Abstract

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virallyinduced T-cell-and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.Coronavirus SARS-CoV-2 is responsible for the world-wide pandemic of Covid-19. At the present time there is no effective documented therapy. "Repurposed" drugs such as Kalera, a mixture of lopinavir and ritonvir, used as protease inhibitors for HIV and SARS, failed in a clinical trial for Covid-19 in China (1). Hydroxychloroquine, a malaria drug, also failed in a recent clinical trial in China (2). Ramdesivir an adenosine analog tested for Ebola on monkeys is being tested for Covid-19 (3). The in vitro activity of ramdesivir and hydroxychloroquine against SARS-CoV-2 is at micro-molar concentrations, which are quite high, indicating possible toxicity in vivo ( 4). An influenza drug called Arbidol (umifenovir) was not able to improve the clinical outcome of Covid-19 patients in China (5). Arbidol is an inhibitor that blocks the fusion of the influenza virus with the cell and is active against coronavirus in vitro (5). Tocilizumab (6), which targets the IL-6 receptor, is being tested for Covid-19-induced cytokine storm. A mesenchymal stem-cell therapy is also being tested for Covid-19 (7).SARS-Cov-2 is a positive single-stranded RNA virus which uses its genomic RNA both for translation and replication (8-11). For proper RNA replication and translation, the cap of the viral RNA must be methylated (8-14). It appears that two methylation sites are present in the viral RNA of coronaviruses; one site is necessary for replication and translation, and the other site possibly for the viral RNA to evade the host intracellular immunity system which would degrade the RNA if not for the cap methylation (8-14). For example, Wang et al. showed that a designed peptide named TP29 targeted the 2'-Omethyltransferase of co...

Amino acid metabolism and signalling pathways: potential targets in the control of infection and immunity

“…Moreover, the coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups provided by S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of Met availability in the host to form SAM and it has been proposed to restrict Met availability by treating Covid-19 patient with oral recombinant methioninase [ 79 ]. Restricting Met not only inhibits viral replication, which depends on the viral RNA cap methylation, but also inhibits the proliferation of the infected cells, which have an increased requirement for Met.…”

An Altered Metabolism in Leukocytes Showing in vitro igG Memory From SARS-CoV-2-Infected Patients

“…To our results, the strong increase of AdoHcy allowed us to postulate an inhibition of s-adenosyl-L-homocysteine hydrolase, and consequently, imbalance of SAM/AdoHcy ratio. Furthermore, the restricted level of methionine availability may inhibit or eliminate the replication as well as prevent proliferation of cells infected with SARS-CoV-2 ( Hoffman and Han, 2020 ). Hence, It is also conceivable to conclude that blocking capping viral mRNAs could be an initial step to developing therapeutics that could help the antiviral therapies.…”

Plasma S-Adenosylmethionine Is Associated with Lung Injury in COVID-19

“…Synthetic inhibitors of N7-Mtase and 2 ′ -OMTase are considered as promising antiviral drugs [23][24][25]. It was also proposed to use the restriction of the bioavailability of methionine as the main substrate for the synthesis of SAM by treating a COVID-19 patient with oral recombinant methioninase [26].…”