Miglustat: A glycotransferase inhibitor for Covid-19 treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) undergoes blood type specific glycosylation which has implications for infection susceptibility and replication without detection from the immune system. SARS-CoV-2 hijacks the host cell glycotransferase resulting in spike protein glycosylation resembling blood type antigens. Infection risk correlates to blood types that do not have anti-A and/or anti-B antibodies similar to that seen for ABO blood type recipients. The universal recipient AB is highly susceptible to infection lacking both anti-A and B antibodies, whereas blood type O has both antibodies resulting in less risk of infection. Once infected, SARS-CoV-2 obtains the blood type specific glycosylation of the host resulting in an effective camouflage against immune system recognition. Decoding the link between blood type and coronavirus disease 2019 (COVID-19) susceptibility exposes a role for miglustat a glycosyltransferase inhibitor in treatment. Use of the FDA-approved glycosyltransferase inhibitor miglustat can inhibit spike protein glycosylation revealing the SARS-CoV-2 virus for immune system recognition.


INTRODUCTION
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main protein used in many vaccines, revealing its importance in immune system recognition of the SARS-CoV-2 virus.A recent paper by Grant et.al.   showed the SARS-CoV-2 spike protein surface is highly shielded by glycans preventing antibody recognition. 1 Since the virus hijacks the host cellular machinery, spike protein glycosylation would obtain a host blood type glycan surface.As mentioned by Grant et al the viral glycan shield may be composed of familiar host glycans. 1 Another study dealing with SARS-CoV-1 has indicated glycotransferase activity resulting in A antigen variant of the ABO blood group with anti-A antibodies able to cause virus neutralization. 2Infection susceptibility may therefore be related to the ABO blood type recipients, and once infected the SARS-CoV-2 would obtain the host cell glycosylated coat becoming blood type specific.
The ABO blood-type is determined by the type of glycosylation found on the surface of red blood cells.The enzymes responsible for blood type glycosylation are known as glycotransferases. 2 There are four possible blood types A, B, O and AB while the Rh system is either Rh positive or negative. 3Blood-typing identifies individuals who are recipients and/or donors of red blood cells.Blood type recipients lack antibodies to donor red blood cells with AB+ known as universal recipients. 3While donors lack either A and or B surface antigens glycosylation making O-individuals known as universal donors. 3The relationship to blood type and covid-19 has been demonstrated by many papers with blood type O found to have a decreased risk of morbidity and mortality associated with coronavirus disease 2019 (Covid-19) 4,5,6 .The impact of glycosylation on the ability of antibodies to bind the SARS-CoV-2 spike protein plays a role not only in infection susceptibility but also in replication without detection by the immune system.
In this paper a new antiviral mechanism of action is proposed for miglustat that is different from inhibition of receptor binding. 7,8A main feature of SARS-Cov-2 is the avoidance of immune recognition by the protective glycan coat. 1 The mechanism of action purpose in this paper of miglustat is treatment of SAR-CoV-2 by the removal of the protective glycan coat exposing the virus to immune system recognition (Figure 1).Miglustat is a FDA approved drug for the treatment of Gaucher disease and Niemann-Pick disease type C because of its alpha-glucosidase inhibition. 9Miglustat was shown to decrease the intracellular accumulation of glycosylcereride the glycolipid that accumulates in Gaucher disease.Sideeffects with miglustat are common and included diarrhea, weight loss, gastrointestinal upset, nausea and vomiting, anorexia, constipation, headache, tremor, dizziness, paresthesia, peripheral neuropathy, ataxia, visual problems, and memory loss. 9Side-effects are manageable since treatment duration with miglustat may be between 3-10days to correlate with the viral replication window.

DISCUSSION
The relationship of blood type susceptibility to SARS-CoV-2 infection is a result of host cell blood type glycosylation of the virus. 4,5,6The SARS-CoV-2 spike protein obtains a similar glycan coat as red blood cells, and infection susceptibility becomes related to blood type recipients.An AB blood type is universally susceptible to SARS-CoV-2 similar to the universal recipient status of AB whereas blood type O has less risk of infection.Reports have shown blood groups A or AB are at increased risk from SARS-CoV-2 infection versus those of blood group O an B. 4,5,6 These results correlated with those seen in table 1 where AB and A have 100% to 88% susceptibility respectively to SARS-CoV-2, whereas blood- The evaluation of miglustat Covid-19 treatment effectiveness was previously investigated In Vitro revealing that it is unlikely to impact the course of the disease. 8In a paper by Nunes-Santos et al, Miglustat treatment had no impact on receptor binding of SARS-CoV-2 spike protein to the ACE2 receptor, in addition there was no effect on cytokine production in stimulation of PBMC. 8Understanding the relationship between blood type and SARS-Cov-2 infection susceptibility and replication without immune system recognition reveals a mechanism for treatment.Alternatively, our proposed mechanism of action for miglustat is the prevention of glycan coat formation on the SARS-CoV-2 spike protein allowing for immune system recognition.In vivo SARS-CoV-2 spike protein glycosylation prevents immune system recognition. 1The In Vitro models by Nunes-Santos et al do not reflect that seen In Vivo, since HEK293T cells used to produce the spike The implication of extensive SARS-CoV-2 glycosylation is seen in the increased severity of Covid-19 in diabetic patients with high hemoglobin A1C. 10 A study by Merzon et al showed pre-infected patients with a hemoglobin A1C of greater than 9% was a risk factor for Covid-19 severity. 10As with diabetic individuals where high hemoglobin A1C results in more extensive glycosylation of red blood cells, SARS-CoV-2 spike protein may be further glycosylated in this environment.Increased SARS-CoV-2 spike protein glycosylation would lead to an improved virus glycan shield, providing an effective barrier against immune system recognition.

RESULTS
Table 1.Susceptibility to SAR-Cov-2 based on recipient blood types and their percentage represented in the population.

2 .
type B and O are less susceptible with 55% and 46%, respectively.The anti-A and anti-B antibodies of blood type O individuals provide a barrier to infection from A, B, and AB blood type individuals infected with SARS-CoV-2.However, blood type O individuals can become infected by SARS-CoV-2 infected blood type O individuals.Once an individual is infected by SARS-CoV-2 they produce viruses with glycans matching the host blood type.The spike protein glycosylation of SARS-CoV-2, provides the virus with an effective camouflage against host immune system recognition. 1A blood type O individual can thus infect a blood type A individual, with the resultant virus replication producing blood type A SARS-CoV-Blood type association with SARS-Cov-2 infection is underlined by virus hijacking host cell machinery enzymes involved in blood type glycosylation by glycotransferases indicating inhibition of these enzymes as a possible treatment for covid-19.
Qeios, CC-BY 4.0 • Article, January 30, 2021 Qeios ID: PE4TSQ.2 • https://doi.org/10.32388/PE4TSQ.2 3/7 protein glycosylation are immunologically different from the peripheral blood mononuclear cells (PBMCs).Therefore, experiments revealing no difference in cytokine production with and without miglustat treatment are comparing two antigenic proteins.However, there is evidence from Ninues-Santos et al showing the SARS-Cov-2 protein is modified by miglustat and this modification produces an immune response. 8Thus, it is possible for miglustat to be an effective treatment for Covid-19 by allowing for immune system recognition of the SARS-Cov-2 spike protein.Miglustat antiviral mechanism of actions lies in the glycotransferase inhibition of SARS-CoV-2 spike protein glycosylation, which exposes the spike protein to immune recognition.The FDA approved dosage of miglustat for treatment of Gaucher disease is 100mg three times a day and Niemann-Pick Type C disease is 200mg three times day. 9